Clinicopathological features and prognostic validity of WHO grading classification of SINENs

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Chen et al. BMC Cancer (2017) 17:521 DOI 10.1186/s12885-017-3490-3 RESEARCH ARTICLE Open Access Clinicopathological features and prognostic validity of WHO grading classification of SINENs Luohai Chen1, Lin Zhou2, Meng Zhang2, Liang Shang3, Panpan Zhang4, Wei Wang5, Cheng Fang5, Jingnan Li6, Tianming Xu6, Huangying Tan7, Pan Zhang7, Meng Qiu8, Xianjun Yu9, Kaizhou Jin9, Ye Chen10, Huishan Chen10, Rong Lin11, Qin Zhang12, Lin Shen4, Minhu Chen1, Jie Li4*, Leping Li3* and Jie Chen1* Abstract Background: The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients. Methods: 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied. Results: Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in nonampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs. Conclusions: Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs. Keywords: Neuroendocrine neoplasms, Small intestine, Clinicopathological characteristics, Tumor grade * Correspondence: chen0jie@hotmail.com; lileping@medmail.com.cn; xiaotong10241@sina.com Luohai Chen and Lin Zhou contributed equally to this work. Jie Chen, Leping Li and Jie Li contributed equally to this work. 4 Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis & Translational Research under Ministry of Education, Peking University Cancer Hospital & Beijing Cancer Hospital, No.52 Fucheng Road, Haidian District, Beijing 100142, China 3 Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, No.324 Jingwu Road, Huaiyin District, Jinan 250021, China 1 Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan II Road, Yuexiu District, Guangzhou 510080, China Full list of author information is available at the end of the article Background Small intestinal neuroendocrine neoplasms (SI-NENs) is a rare group of malignancies originating from duodenum, jejunum and ileum. Epidemiologic studies from United States and European countries indicate that the incidence of NENs has been rising significantly while small intestine is the most common location of digestive NENs which accounts for 30%–41% of digestive NENs with an age-standardized incidence rate of 0.86/100,000 [1, 2]. However, unlike those in western population, SINENs is much rarer in Asian population. An epidemiologic study from Taiwan showed that SI-NENs accounted for 9% of digestive NENs with an age-standardized © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. BMC Cancer (2017) 17:521 incidence rate of 0.06/100,000 [3]. Our former single center study revealed that in 178 patients with digestive NENs, only 17 patients (9.5%) had disease located in small intestine [4]. Another nation-wide epidemiologic study of China showed that SI-NENs consisted of only 5.6% of gastroenteropancreatic NENs [5]. Because of the low incidence rate of SI-NENs, clinicopathological characteristics of SI-NENs are still unknown in Asian population. The current widely used pathological classification for digestive NENs was firstly proposed by European Neuroendocrine Tumor Society (ENETS) and endorsed by World Health Organization (WHO) in 2010 [6, 7]. This WHO grading classification distinguishes NENs into three grades (grade 1, grade 2 and grade 3) according to tumor differentiation, Ki-67 index and mitotic count. Studies from western countries indicated that patients with grade 3 disease had worse outcome compared with patients with grade 1/2 disease [8, 9]. Nevertheless, Ki67 index of 2% as the threshold differentiating grade 1 and grade 2 disease is challenged by a number of studies. In pancreatic NENs, studies suggested that Ki-67 index of 5% was a better threshold than 2% between grade 1 and grade 2 to predict survival of patients [10, 11]. Study from Khan, et al. also suggested that the thereshold to classify grade 1 and grade 2 should be revised from 2% to 5% both in pancreatic and midgut NENs including NENs of lower jejunum, ileum and appendix [12]. Since Ki-67 index threshold to differentiate grade 1 and grade 2 remained controversial, and there are few studies investigating the prognostic validity of WHO grading classification in the whole small intestine including duodenum jejunum and ileum in Asian patients, whether this grading criteria is appropriate for outcome prediction in SI-NENs of Asian patients is still unclear. The goals of our study are to investigate the clinicopathological characteristics of Chinese patients with SINENs by comparing with patients from Surveillance, Epidemiology, and End Results (SEER) cancer registry, and to investigate the prognostic validity of the WHO grading classification for SI-NENs using a multicenter cohort from China. Methods Patients and data collection Clinical data of patients with pathologically confirmed SI-NENs from January 2000 to July 2016 was retrieved from eleven Chinese hospitals including The First Affiliated Hospital, Sun Yat-sen University (n = 49), The First Affiliated Hospital of Zhengzhou University (n = 36), Shandong Provincial Hospital Affiliated to Shandong University (n = 34), Peking University Cancer Hospital (n = 31), Sun Yat-sen University Cancer Center (n = 26), Peking Union Medical College Hospital (n = 25), ChinaJapan Friendship Hospital (n = 24), West China Hospital Page 2 of 11 of Sichuan University (n = 17), Fudan University Shanghai Cancer Center (n = 12), Nanfang Hospital, Southern Medical University (n = 12), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (n = 11). These eleven hospitals respectively located in the north, central, west, east and south of China and all of these hospitals were representative general hospitals or cancer centers in their regions. NENs grown in ampullary region were also included in this study as a part of duodenal NENs. Patients who had previous or concomitant other kinds of cancer or documented hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN-1) were excluded. We also retrieved data of patients with SI-NENs from the SEER database. We selected all NENs of the small intestine (site code: C17.0 to C17.9) and ampulla of Vater (site code: C24.1) from the SEER database. The following ICD-O-3 histology codes were applied to identify SI-NENs including: 8013, 8150–8156, 8240–8249. Only patients diagnosed with positive pathology after 2000 were included in this study. Patients with a history of other cancers or diagnosed at autopsy or on death certificate were excluded. Data including age at diagnosis, sex, date of initial diagnosis, location of primary tumor, tumor differentiation, tumor size and extension, nodal status, location of distant metastasis, follow-up data and surgery of primary tumor were retrieved from both the Chinese cohort and SEER database. Surgery of primary tumor included endoscopic resection, local excision, total resection, debulking surgery, et al. Other information including presenting symptoms, tumor grade according to WHO 2010 classification based on Ki-67 index and mitotic count were also retrieved from the Chinese cohort. In SEER database, tumor grade according to WHO 2010 classification was not available, only tumor differentiation was retrieved. All data were reviewed and checked independently by Luohai Chen and Jie Chen and this study was approved by the institutional review board of the included hospitals. Grading and staging classification Ki-67 index and mitotic count were used for assignment of tumor grade in Chinese patients. Ki-67 index was detected using MIB-1 antibody and counted in areas of strongest nuclear labelling. Mitotic count was evaluated at least 50 HPFs (1HPF = 2 mm2). Higher grade was assigned when discrepancy between Ki-67 index and mitotic count to determine grade existed. Three grades were classified according to the WHO 2010 classification including: Grade 1 (G1, Ki-67 index ≤ 2% and/or mitotic count<2/10HPF), Grade 2 (G2, Ki-67 index: 3–20% and/ or mitotic count: 2–20/10HPF), Grade 3 (G3, Ki-67 index>20% and/or mitotic count>20/10HPF) [13]. All pathological sections were reviewed by specialized expert Chen et al. BMC Cancer (2017) 17:521 pathologists from the included hospitals. Tumor stages were assigned according to the staging classification sequentially proposed by European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) [7, 14, 15] which were identical in NENs of small intestine. Statistical analysis To investigate the basic clinicopathological characteristics of the study patients, student t test, χ2 test (or Fisher exact test) and Mann-Whitney method were used. Survival time was measured from date of initial diagnosis until the date of death or last follow-up. Overall survival (OS) analyses were then performed using Kaplan-Meier analyses with log-rank test. Multivariate analyses were performed using Cox proportional hazards regression with the lowest risk group as the reference group. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. All analyses were carried out by using IBM SPSS statistics 22.0 (IBM, Chicago, IL), while statistical significance was defined as a 2-sided P < 0.05. Results Comparison of the clinical characteristics of SI-NENs in different races In total, 277 patients and 8315 patients with SI-NENs were included respectively from the Chinese cohort and SEER database (Table 1). The clinical characteristics of SI-NENs among different races were different. The mean ages were 54.4, 62.4, 60.3 and 60.7 respectively in Chinese, white, black patients and Asian/Pacific Islander (AP) patients. Except for black patients, male patients were more common. Duodenum was the predominant primary tumor site of SI-NENs in Chinese (76.5%) and AP patients (71.9%). But in white patients, jejunal/ileal NENs was more common (68.1%). In Chinese patients, tumor size was significantly larger than that in other groups of patients. Compared with white patients (28.2%), stage I/II were common in Chinese patients (49.8%), black patients (39.3%) and AP patients (47.2%). Surgery of primary tumor was performed in most of the patients in different race patients. In Chinese patients, the most common presenting symptom was abdominal pain which occurred in 54.9% of patients. Carcinoid syndrome was rare. Only five patients manifested both diarrhea and flushing. 35 patients (12.6%) were diagnosed incidentally without distinct symptoms. Liver was the most common location of distant metastases (86.7%). As for tumor grade, 36.5%, 32.5%, 30.9% of patients had G1, G2 and G3 disease respectively. However, in SEER database, only 5.2% of white, 4.3% of black patients and 9.7% of AP patients had poorly differentiated/undifferentiated disease. Page 3 of 11 Comparison of duodenal and jejunal/ileal NENs Since the tumor location of SI-NENs among different races were significantly different, we then compared the clinical characteristics between duodenal and jejunal/ ileal NENs (Table 2). In Chinese patients, tumor size of duodenal NENs (median: 2.0 cm) was significantly smaller than that of jejunal/ileal NENs (median: 3.0 cm). Tumor grades between duodenal NENs and jejunal/ileal NENs were not significantly different. Patients with duodenal NENs were inclined to have T1 (20.1%) and T2 disease (39.6%). Furthermore, duodenal NENs had a lower metastatic rate of lymph nodes compared to that of jejunal/ileal NENs (32.4% vs. 62.7%, P < 0.001). Similarly, distant metastasis was less common in duodenal NENs than that in jejunal/ileal NENs but it was not statistically significant. Hence, stage I and stage II were more common in duodenal NENs (P < 0.001). In patients from SEER database, similar results were found (Table 2). Tumor size was also significantly smaller and T1, T2, stage I and stage II were also more common in patients with duodenal NENs than jejunal/ ileal NENs. Both metastatic rate of lymph nodes and distant location were significantly lower in duodenal NENs compared with jejunal/ileal NENs. The mean age of patients with duodenal NENs were older than patients with jejunal/ileal NENs both in white and black patients but not in AP patients. Additionally, in white patients but not black and AP patients, poorly differentiated tumor was more common in duodenal NENs compared with jejunal/ileal NENs (9.6% vs. 3.5%). Comparison of ampullary and non-ampullary duodenal NENs We further compared the clinicopathological features of ampullary NENs and non-ampullary NENs (Table 3). In Chinese patients, the most common symptoms of patients with ampullary NENs were abdominal pain, followed by jaundice. While in non-ampullary duodenal NENs, jaundice was less common. G3 disease (47.6%) was more common and tumor size (median, 2.5 cm) was larger in ampullary NENs compared with non-ampullary duodenal NENs. Patients with ampullary NENs tended to have more T3 and T4 disease. However, ampullary NENs did not show more metastases to lymph nodes (N1) and distant location (M1) compared with nonampullary duodenal NENs. Due to the small sample size of ampullary NENs in AP patients, the comparison of ampullary and non-ampullary duodenal NENs was not performed. In white and black patients from SEER database, the mean age of patients with ampullary NENs was younger than that of nonampullary duodenal NENs. Tumor size of ampullary NENs was also significantly larger. Ampullary NENs tended to be more aggressive that T3, T4, N1 and M1 Chen et al. BMC Cancer (2017) 17:521 Page 4 of 11 Table 1 Comparison of the clinical characteristics of SI-NENs among different races Characteristics Chinese Patients (N = 277) SEER database White patients (N = 6711) P value Black patients (N = 1387) Asian/Pacific Islander Patients (N = 217) Age, years <0.001 Mean(95%CI) 54.4 (52.8–56.0) 62.4 (62.0–62.7) 60.3 (59.6–61.0) 60.7 (59.0–62.5) Range 17–83 2–98 21–96 27–95 Male 157 (56.7%) 3448 (51.4%) 635 (45.8%) 116 (53.5%) Female 120 (43.3%) 3263 (48.6%) 752 (54.2%) 101 (46.5%) Sex <0.001 Location of primary tumora <0.001 b Duodenum 212 (76.5%) 1541 (31.9%) 569 (57.5%) 123 (71.9%) ampulla 72 (37.1%) 117 (7.6%) 24 (4.2%) 9 (7.3%) Non-ampulla 122 (62.9%) 1424 (92.4%) 545 (95.8%) 114 (92.7%) Jejunum/ileum 65 (23.5%) 3283 (68.1%) 420 (42.5%) 48 (28.1%) Presenting Symptoms Abdominal pain 152 (54.9%) Nausea/vomiting 48 (17.3%) Bloating 42 (15.2%) Jaundice 37 (13.4%) GI bleeding 34 (12.3%) Diarrhea 27 (9.7%) Intestinal obstruction 24 (8.7%) Flushing 9 (3.2%) Incidental diagnosis - Yes 35 (12.6%) No (symptomatic) 242 (87.4%) c Tumor size <0.001 Median (cm) 2.5 1.6 1.5 1.5 Tumor graded - Grade 1 91 (36.5%) Grade 2 81 (32.5%) Grade 3 77 (30.9%) e 0.095f Tumor differentiation Well differentiated 2324 (76.6%) 474 (81.3%) 69 (74.2%) Moderately differentiated 553 (18.2%) 84 (14.4%) 15 (16.1%) Poorly differentiated/undifferentiated 157 (5.2%) 25 (4.3%) 9 (9.7%) Tumor stageg <0.001h I 32 (13.3%) 626 (13.2%) 162 (18.3%) 43 (25.4%) II 88 (36.5%) 709 (15.0%) 186 (21.0%) 28 (16.6%) III 61 (25.3%) 2077 (43.8%) 331 (37.4%) 59 (34.9%) IV 60 (24.9%) 1329 (28.0%) 205 (23.2%) 39 (23.1%) Location of distant metastasesi - No 217 (78.3%) Liver 52 (86.7%) Chen et al. BMC Cancer (2017) 17:521 Page 5 of 11 Table 1 Comparison of the clinical characteristics of SI-NENs among different races (Continued) Bone 3 (5.0%) Lung 1 (1.7%) Brain 1 (1.7%) Others 13 (21.7%) Surgery of primary tumor - Performed 233 (84.1%) 5787 (86.2%) 1097 (79.1%) 166 (76.5%) Unperformed or unknown 44 (15.9%) 924 (13.8%) 290 (20.9%) 51 (23.5%) GI gastrointestinal. aThe specific location of 1887 white patients, 398 black patients and 46 Asian/Pacific Islander patients from SEER database were not available. b In Chinese patients, the specific location of 18 patients with duodenal NENs was unknown. cTumor size was specified in 222 Chinese patients, 5249 white patients, 1008 black patients and 151 Asian/Pacific Islander patients from SEER database. dTumor grade based on WHO grading criteria was specified in 249 Chinese patients. eIn SEER database series, tumor differentiation was available in 3034 white patients, 583 black patients and 93 Asian/Pacific Islander patients. f Well/moderately differentiated and poorly differentiated/undifferentiated were compared among different races. gTumor stage was specified in 241 Chinese patients, 4741 white patients, 884 black patients and 169 Asian/Pacific Islander patients from SEER database. hStage I/II and stage III/IV were compared among different races. iInformation of location of distant metastases was available in all Chinese patients Tumor grade and survival analyses of potential factors of OS. Factors which were statistically significant associated with OS in univariate analyses were included in the multivariate analyses. Multivariate analysis showed that, G2 was a significant factor indicating poorer survival when Ki-67 index of 5% but not 2% as threshold (Table 4). In addition, stage IV was also an independently prognostic factor indicating worse survival (Table 4). Tumor grade according to WHO 2010 classification was available in Chinese patients but not in patients from SEER database. Hence, the prognostic validity of WHO grading classification was analyzed only in Chinese patients. 207 patients with survival information including 160 patients (77.3%) with duodenal NENs and 47 patients (22.2%) with jejunal/ileal NENs were retrieved. The mean follow-up time was 24.3 months (95%CI, 20.9 to 27.6 months). The 5-year overall survival (OS) rates of G1, G2 and G3 were 91.7% (95%CI, 83.9% to 99.5%), 76.6% (95%CI, 60.5% to 92.7%) and 32.9% (95%CI, 18.4% to 47.4%) respectively. The survival rate of patients with G3 was significantly worse than that of patients with G1 and G2 (G3 vs. G1, P < 0.001; G3 vs. G2, P < 0.001). However, survival rate of patients with G1 and G2 was not significantly different (G2 vs. G1, P = 0.132). Multivariate analysis adjusting for age, sex, tumor location, tumor stage revealed similar results (G2 vs. G1, HR 1.89, 95%CI, 0.57 to 6.28, P = 0.301; G3 vs. G1, HR, 11.48, 95%CI, 3.91 to 33.69, P < 0.001). Previous studies suggested Ki-67 index of 5% as the threshold between G1 and G2 disease in pancreatic and midgut NENs [11, 12]. In our study, we also investigated whether 2% or 5% was the better threshold between G1 and G2. With Ki-67 index of 2% as threshold, Kaplan-Meier analysis with log-rank test did not show significantly different result between G1 and G2 (P = 0.091; Fig. 1a). With Ki-67 index of 5% as threshold, G2 had significantly worse survival compared with G1 (Fig. 1b; P = 0.004). Table 4 showed the results of Discussion In this study, we collected a series of patients with SINENs from eleven Chinese hospitals which was the largest series from Asia. We found that the clinicopathological characteristics of SI-NENs in different races were different. One of the most distinct characteristics we found was that the rate of duodenal NENs was significantly higher in Chinese patients than that in white and black patients from SEER database. This situation was also found in AP patients with SI-NENs from SEER database. Therefore, the most potential cause might be genetic differences among different races. The most common manifestation was abdominal pain in Chinese patients while carcinoid syndrome with flushing and diarrhea was much rarer. This might because most of Chinese patients having NENs located in duodenum while carcinoid syndrome mostly occurred in patients with advanced NENs of distal small intestine [16]. We also found that G3 disease (mostly poor differentiation) was more common in Chinese SI-NENs patients while less than 10% of white, black and AP patients from SEER database had poorly differentiated tumor. Patients with ampullary NENs in the Chinese series were more common than that from SEER database. Furthermore, ampullary NENs had more G3 disease compared with other location. This might partly explain the high frequency of G3 disease in Chinese patients. The clinicopathological characteristics of duodenal NENs and jejunal/ileal NENs were also different. In the disease were more common than that in non-ampullary duodenal NENs. Therefore, stage III and IV disease were more common in ampullary NENs. Additionally, in white patients, poorly differentiated NENs consisted of a larger proportion (36.5%) in ampullary NENs than that in nonampullary duodenal NENs (6.7%). 60 (31.4%) Grade 3 12 (7.1%) T4 75 (41.0%) 37 (20.2%) 41 (22.4%) II III IV 19 (32.8%) 24 (41.4%) 13 (22.4%) <0.001 0.090 <0.001 91 (11.1%) 129 (15.8%) 190 (23.3%) 407 (49.8%) 817d 91 (7.0%) 1217 (93.0%) 1308d 178 (13.4%) 1154 (86.6%) 1332 d 52 (5.8%) 62 (7.0%) 279 (31.3%) 497 (55.8%) 890d 764 (30.0%) 1347 (52.9%) 305 (12.0%) 132 (5.2%) 2548e 764 (28.6%) 1908 (71.4%) 2672e 2216 (70.4%) 930 (29.6%) 3146 e 648 (25.3%) 1044 (40.8%) 584 (22.8%) 283 (11.1%) 2559e 58 (3.5%) 321 (19.5%) 1268 (77.0%) 1647e 1.9 1652 (50.3%) 1631 (49.7%) 60.2–61.1 60.7 Jejunum/ileum <0.001 <0.001 <0.001 <0.001 <0.001 - <0.001 0.914 <0.001 P 24 (8.8%) 40 (14.7%) 75 (27.5%) 134 (49.1%) 273f 24 (5.2%) 434 (94.8%) 458f 58 (12.1%) 421 (87.9%) 479 f 9 (3.0%) 17 (5.7%) 109 (36.3%) 165 (55.0%) 300f 9 (4.0%) 43 (19.3%) 171 (76.7%) 223f 1.0 305 (53.6%) 264 (46.4%) 61.7–63.8 62.7 Duodenum Black patients 86 (26.1%) 175 (53.0%) 53 (16.1%) 16 (4.8%) 330g 86 (24.4%) 267 (75.6%) 353g 259 (64.6%) 142 (35.4%) 401 g 76 (22.4%) 128 (37.8%) 102 (30.1%) 33 (9.7%) 339g 8 (4.0%) 25 (12.4%) 169 (83.7%) 202g 1.9 233 (55.5%) 187 (44.5%) 56.1–58.3 57.2 Jejunum/ileum <0.001 <0.001 <0.001 <0.001 0.149 - <0.001 0.559 <0.001 P 7 (9.2%) 15 (19.7%) 20 (26.3%) 34 (44.7%) 76h 7 (5.9%) 112 (94.1%) 119h 15 (13.8%) 94 (86.2%) 109 h 5 (6.9%) 6 (8.3%) 27 (37.5%) 34 (47.2%) 72h 5 (10.6%) 4 (8.5%) 38 (80.9%) 47h 1.0 63 (51.2%) 60 (48.8%) 60.0–65.0 62.5 Duodenum 12 (25.5%) 23 (48.9%) 7 (14.9%) 5 (10.6%) 47i 12 (25.0%) 36 (75.0%) 48i 32 (68.1%) 15 (31.9%) 47i 10 (26.3%) 14 (36.8%) 9 (23.7%) 5 (13.2%) 38i 2 (9.5%) 5 (23.8%) 14 (66.7%) 21i 1.5 22 (45.8%) 26 (54.2%) 55.6–62.8 59.2 Jejunum/ileum Asian/Pacific Islander patients 0.232 0.001 0.527 0.157 <0.001 <0.001 <0.001 <0.001 - P a Tumor grade was based on WHO 2010 classification criteria (grade 1, 2 and 3) in Chinese patients. b,cThe number available in Chinese SI-NENs patients with 212 patients of duodenal NENs and 65 patients of jejunal/ileal NENs in total. d,eThe number available in SEER database with 1541 white patients of duodenal NENs and 3283 white patients of jejunal/ileal NENs in total. f,gThe number available in SEER database with 569 black patients of duodenal NENs and 420 black patients of jejunal/ileal NENs in total. h, iThe number available in SEER database with 123 Asian/Pacific Islander patients of duodenal NENs and 48 Asian/Pacific Islander patients of jejunal/ileal NENs 30 (16.4%) I 2 (3.4%) 58c 183b Tumor stage 19 (29.2%) 46 (70.8%) 41 (19.3%) 65c 212b 171 (80.7%) 37 (62.7%) 61 (32.4%) M1 22 (37.3%) 127 (67.6%) 59 c 6 (11.3%) 35 (66.0%) 9 (17.0%) 3 (5.7%) M0 M status N1 N0 188 56 (33.1%) T3 N status 67 (39.6%) T2 b 34 (20.1%) T1 <0.001 63 (9.6%) Poorly or undifferentiated T status 98 (14.9%) 658d 497 (75.5%) - 0.227 1.0 778 (50.5%) 763 (49.5%) Moderately differentiated 53c 17 (29.3%) 24 (41.4%) 17 (29.3%) 58c <0.001 0.041 63.3 62.6–64.0 Well differentiated 169b 57 (29.8%) Grade 2 Tumor differentiation 74 (38.7%) Grade 1 191b Tumor gradea 3.0 21 (32.3%) 99 (46.7%) 2.0 44 (67.7%) Median Tumor size, cm Female Male 53.3 50.1–56.50 113 (53.3%) 52.9–56.6 Sex 54.7 95%CI 0.452 Duodenum Mean Age, years White patients P Duodenum Jejunum/ileum Chinese Patients Table 2 Comparison of the clinical characteristics between duodenal and jejunal/ileal NENs Chen et al. BMC Cancer (2017) 17:521 Page 6 of 11 72a 2 (1.6%) 122b 5 (6.9%) 8 (11.1%) 3 (4.2%) 4 (5.6%) 2 (2.8%) 72a Bloating GI bleeding Diarrhea Intestinal obstruction 4 (6.7%) 20 (33.3%) T1 T2 T status 95 39 (41.1%) 29 (30.5%) <0.001 39 (50.0%) 15 (19.2%) 78 23 (36.5%) c 12 (19.0%) Poorly or undifferentiated 63 c Moderately differentiated - 0.003 0.386 1.8 86 c 57 (48.7%) 60 (51.3%) 117c 31–87 59.7 (57.1–62.3) 28 (44.4%) b 25 (22.3%) 39 (34.8%) 48 (42.9%) 112b 103 (84.4%) 19 (15.6%) 11 (9.0%) 16 (13.1%) 23 (18.9%) 17 (13.9%) <0.001g - 0.010 0.337 0.961 Well differentiated 60 30 (47.6%) Grade 3 a 15 (23.8%) Grade 2 Tumor differentiation 18 (28.6%) 63 Grade 1 Tumor grade 64 (88.9%) No (symptomatic) a 8 (11.1%) Yes Incidental diagnosis Flushing 3 (2.5%) 8 (11.1%) Nausea/vomiting 7 (5.7%) 26 (36.1%) Jaundice 63 (51.6%) 122b 72a 34 (47.2%) 1.6 93 2.5 61 b 54 (44.3%) Abdominal pain Presenting Symptoms Median Tumor size, cm 37 (51.4%) Female a 35 (48.6%) Male 68 (55.7%) 17–80 122b 25–81 Range Sex 54.9 (51.9–58.0) 54.8 (52.3–57.4) White patients P Ampullary NENs Non-ampullary duodenal NENs Chinese patients Ampullary NENs Mean (95%CI) Age, years Characteristics d 240 (29.6%) 482 (59.4%) 812 d 40 (6.7%) 86 (14.5%) 469 (78.8%) 595 0.9 851 d 721 (50.6%) 703 (49.4%) 1424d 13–97 63.6 (62.9–64.3) Non-ampullary duodenal NENs Table 3 Comparison of the clinical characteristics between ampullary and non-ampullary duodenal NENs <0.001 <0.001 - - <0.001 0.691 0.003 P Black patients 15 13 (68.4%) 3 (15.8%) 19 e 2 (13.3%) 3 (20.0%) 10 (66.7%) e 2.2 21 e 11 (45.8%) 13 (54.2%) 24e 34–80 57.1 (52.5–61.7) Ampullary NENs f 96 (34.2%) 162 (57.7%) 281f 8 (3.8%) 40 (19.1%) 161 (77.0%) 209 1.0 312f 294 (53.9%) 251 (46.1%) 545f 21–94 63.0 (61.9–64.0) Non-ampullary duodenal NENs 0.002 0.177 - - <0.001 0.435 0.028 P Chen et al. BMC Cancer (2017) 17:521 Page 7 of 11 a, b 23 (35.9%) 8 (12.5%) III IV 26 (25.5%) 26 (25.5%) 11 (10.8%) 39 (38.2%) <0.001 0.071 0.535 23 (25.6%) 43 (47.8%) 16 (17.8%) 8 (8.9%) 90c 23 (20.9%) 87 (79.1%) 110 c 46 (47.4%) 51 (52.6%) 97c 15 (19.2%) 9 (11.5%) 68 (9.4%) c,d 86 (11.8%) 174 (23.9%) 399 (54.9%) 727d 68 (5.7%) 1130 (94.3%) 1198 d 132 (10.7%) 1103 (89.3%) 1235d 37 (4.6%) 53 (6.5%) <0.001 <0.001 <0.001 5 (25.0%) 4 (20.0%) 8 (40.0%) 3 (15.0%) 20e 5 (22.7%) 17 (77.3%) 22 e 9 (40.9%) 13 (59.1%) 22e 1 (5.3%) 2 (10.5%) 19 (7.5%) 36 (14.2%) 67 (26.5%) 131 (51.8%) 253f 19 (4.4%) 417 (95.6%) 436f 49 (10.7%) 408 (89.3%) 457f 8 (2.8%) 15 (5.3%) 0.005 0.001 <0.001 GI gastrointestinal. The number available in 72 patients with ampullary NENs and 122 patients with non-ampullary duodenal NENs; The number available in 117 patients with ampullary NENs and 1424 patients with duodenal NENs; e,fThe number available in 117 patients with ampullary NENs and 1424 patients with duodenal NENs; gJaundice was significantly more common in patients with ampullary NENs 30 (46.9%) 64a 3 (4.7%) 26 (21.3%) 102b 8 (11.1%) II 96 (78.7%) 122 b 29 (28.4%) 73 (71.6%) 64 (88.9%) 72 I Tumor stage M1 M0 M status a 23 (32.9%) 102b 70a 47 (67.1%) 6 (6.3%) 6 (10.0%) N1 21 (22.1%) 30 (50.0%) N0 N status T4 T3 Table 3 Comparison of the clinical characteristics between ampullary and non-ampullary duodenal NENs (Continued) Chen et al. BMC Cancer (2017) 17:521 Page 8 of 11 Chen et al. BMC Cancer (2017) 17:521 Page 9 of 11 Fig. 1 Kaplan-Meier analysis of Chinese patients with SI-NENs according to Ki-67 index classification. a With Ki-67 index of 2% as threshold, survival rate of G1 and G2 was not significantly different. b With Ki-67 index of 5% and 20% as threshold between grade 1/2 and grade 2/3 respectively, survival rate among different grades were significantly different Chinese cohort, we found localized disease was more common in duodenal NENs. Tumor size was smaller, while T1, T2, N0 and M0 disease were more common in duodenal NENs. These findings were confirmed by the data from SEER database. The heterogeneities between duodenal and jejunal/ileal NENs indicated that NENs in these two locations might have different biological behaviors which should be managed differently [17, 18]. Since duodenal NENs were quite different from jejunal/ ileal NENs, different distribution of tumor might be one Table 4 Univariate and multivariate analysis of overall survival in patients with SI-NENs: comparison of Ki-67 index 2 and 5% as threshold Factor (N) Univariate analysis Multivariate analysis 2% as threshold Age (207) HR (95% CI) P 1.02 (0.99–1.04) 0.204 Sex HR (95% CI) 5% as threshold P HR (95% CI) P 0.502 Male (121) 1.00 Female (86) 0.82 (0.45–1.48) Location of primary tumor Ampulla (54) 1.00 Non-ampulla duodenum (106) 0.69 (0.35–1.34) 0.272 Jejunum/ileum (47) 0.62 (0.29–1.34) 0.223 Tumor stage 0.002 0.022 Stage I/II (95) 1.00 Stage III (44) 2.43 (1.01–5.87) 0.048 1.89 (0.78–4.58) 0.158 1.90 (0.79–4.61) 0.155 Stage IV (48) 4.68 (2.13–10.27) <0.001 3.44 (1.55–7.62) 0.002 3.29 (1.48–7.31) 0.003 Unknown (20) 2.90 (1.03–8.15) 0.044 2.26 (0.80–6.37) 0.124 2.17 (0.77–6.13) 0.144 Ki-67 index ≤ 2% (80) 1.00 0.033 <0.001 1.00 1.00 <0.001 1.00 3%–20% (63) 2.67 (0.82–8.68) 0.102 2.18 (0.66–7.15) 0.199 > 20% (64) 14.73 (5.20–41.74) <0.001 12.21 (4.26–34.98) <0.001 Ki-67 index <0.001 <0.001 ≤ 5% (118) 1.00 6%–20% (25) 4.29 (1.44–12.76) 0.009 3.28 (1.08–9.98) 0.036 > 20% (64) 12.98 (5.70–29.56) <0.001 11.31 (4.92–26.01) <0.001 1.00 Chen et al. BMC Cancer (2017) 17:521 of the reasons causing different clinicopathological characteristics of SI-NENs among Chinese patients and white and black patients from SEER database. In addition, we found ampullary NENs and nonampullary duodenal NENs shared different characteristics. Since the growth of tumor originating from ampulla or major duodenal papilla might cause obstruction of bile duct, jaundice was one of the most common symptoms of ampullary NENs but not non-ampullary duodenal NENs. Tumor size was significantly larger in ampullary NENs. This might due to the more aggressive nature of ampullary NENs since G3 disease or poorly differentiated tumor were more common in ampullary NENs. In patients from SEER database, metastases of lymph nodes and distant location were more common in ampullary NENs than that in non-ampullary duodenal NENs. However, in Chinese cohort, patients with ampullary NENs did not have more lymphatic or distant metastases than non-ampullary duodenal NENs. Furthermore, ampullary NENs was rare in Asian/Pacific Islander. The potential reason might be that in Chinese cohort, more NENs from periampullary duodenum were included as ampullary NENs in which localized lesion might be more common. It was sometimes challenging to differentiate whether the large periampullary neoplasms were originating from ampulla of Vater or not. WHO grading classification proposed in 2010 is widely used in evaluating prognosis of patients with NENs [8, 11, 19, 20]. In our study, we also confirmed the value of this classification in Chinese SI-NENs patients. G3 disease had significantly worse survival compared with G1 and G2 disease. Ki-67 index threshold to differentiate G1 and G2 remained controversial. A study of midgut NENs revealed Ki-67 index threshold of 2% between G1 and G2 was enough to distinguish patients with different disease specific survival [8]. However, a study of 274 pancreatic NENs indicated that Ki-67 threshold of 5% rather than 2% was an optimal threshold between G1 and G2 disease [11]. This result was confirmed by another study which suggested the threshold between G1 and G2 should be revised from 2% to 5% both in pancreatic and midgut NENs [12]. Another study of duodenal NENs revealed that disease-specific survival of G1 and G2 (with Ki-67 index of 2% as threshold) was significantly different only in univariate analysis but not in multivariate analysis after adjusting for age and stage [21]. In our study, we found Ki-67 index of 5% might be better than 2% to differentiate two groups with significantly different outcome. The result was further verified by multivariate analysis. Therefore, we considered Ki-67 index of 2% as threshold between G1 and G2 was also questionable in Chinese patients with SI-NENs. Limitations still exist in our study. The first limitation is the retrospective nature of our study. But we include Page 10 of 11 more than 270 Chinese patients with SI-NENs which is the largest series from Asia, and we also specify a large sample of patients with SI-NENs from SEER database. The second limitation is that information of Ki-67 index is not available in SEER database so that the result about the WHO grading classification in this study cannot be confirmed by patients from SEER database. Hence, more studies are still required to verify our result. The third limitation is that we compare a Chinese multicenter cohort with a population-based database and there may be a chance of referral bias in the Chinese cohort. To make the Chinese cohort more representative and the referral bias as low as possible, we retrieved data from more than ten representative general hospitals and cancer centers located in different geographical regions of China. Conclusion The clinicopathological characteristics of SI-NENs are quite different among different races which may due to different location of tumor. Duodenum is the predominant location of SI-NENs in Chinese patients and AP patients but not in white patients. Duodenal NENs and jejunal/ileal NENs, ampullary NENs and non-ampullary duodenal NENs also share different clinicopathological features. G3 and stage IV disease are independent factors indicating worse survival. Ki-67 index of 5% may be a better threshold between G1 and G2 in patients with SI-NENs. Abbreviations AJCC: American Joint Committee on Cancer; AP: Asian/Pacific Islander; CI: Confidence interval; ENETS: European Neuroendocrine Tumor Society; HR: Hazard ratio; MEN-1: Multiple endocrine neoplasia type 1; OS: Overall survival; SEER: Surveillance, Epidemiology, and End Results; SI-NENs: Small intestinal neuroendocrine neoplasms; WHO: World Health Organization Acknowledgements The authors thank staff of all centers for their help in collecting data. Funding This work was not funded. Availability of data and materials The data from Chinese patients analyzed during the current study are maintained at the corresponding author. Any reasonable request will be considered but all identifying patient data will be withheld and not be provided. Data from SEER database are available in the Surveillance, Epidemiology, and End Results cancer registry and can also be provided by the corresponding author. Authors’ contributions Jie Chen, Leping Li, Jie Li designed the study. Luohai Chen and Lin Zhou wrote the main manuscript. Jie Chen and Luohai Chen performed the statistical analysis. Meng Zhang, Liang Shang, Panpan Zhang, Wei Wang, Cheng Fang, Jingnan Li, Tianming Xu, Huangying Tan, Pan Zhang, Meng Qiu, Xianjun Yu, Kaizhou Jin, Ye Chen, Huishan Chen, Rong Lin, Qin Zhang collected the data. Lin Shen and Minhu Chen edited the manuscript. All authors have read and approved the manuscript. Ethics approval and consent to participate The ethics approvals were provided by the institutional review board of The First Affiliated Hospital, Sun Yat-Sen University, The First Affiliated Hospital of
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