Access the full text.
Sign up today, get DeepDyve free for 14 days.
K. Nishikura, Hidenobu Watanabe, M. Iwafuchi, T. Fujiwara, K. Kojima, Y. Ajioka (2003)
Carcinogenesis of gastric endocrine cell carcinoma: analysis of histopathology and p53 gene alterationGastric Cancer, 6
T. Kubota, S. Ohyama, N. Hiki, S. Nunobe, N. Yamamoto, Toshiharu Yamaguchi (2012)
Endocrine carcinoma of the stomach: clinicopathological analysis of 27 surgically treated cases in a single instituteGastric Cancer, 15
Chun-Wei Peng, Linwei Wang, Wei-Juan Zeng, Xiaojun Yang, Yan Li (2013)
Evaluation of the staging systems for gastric cancerJournal of Surgical Oncology, 108
C. Otis (2011)
Quality assurance for design control and implementation of immunohistochemistry assays; Approved guidelinesecond edition
M. Chen, Y. Kuo, Y. Yeh, Ying-Chu Lin, C. Tzeng, Chun-Yu Liu, P. Chang, Ming-Han Chen, Y. Jeng, Y. Chao (2015)
High neuroendocrine component is a factor for poor prognosis in gastrointestinal high‐grade malignant mixed adenoneuroendocrine neoplasmsJournal of the Chinese Medical Association, 78
H. Waldum, S. Aase, I. Kvetnoi, E. Brenna, A. Sandvik, U. Syversen, Gjermund Johnsen, L. Vatten, J. Polak (1998)
Neuroendocrine differentiation in human gastric carcinomaCancer, 83
F. Eren, Ç. Çelikel, B. Güllüoğlu (2008)
Neuroendocrine differentiation in gastric adenocarcinomas; correlation with tumor stage and expression of VEGF and p53Pathology & Oncology Research, 10
S. Rosa, A. Marando, F. Sessa, C. Capella (2012)
Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An UpdateCancers, 4
F. Bosman (2010)
WHO Classification of Tumours of the Digestive System
Jian-Wei Xie, Jun Lu, Jian-Xian Lin, C. Zheng, Ping Li, Jia-Bin Wang, Qi-Yue Chen, L. Cao, Mi Lin, R. Tu, Chang-ming Huang (2017)
Different long-term oncologic outcomes after radical surgical resection for neuroendocrine carcinoma and adenocarcinoma of the stomachOncotarget, 8
Angela Bartley, A. Rashid, K. Fournier, S. Abraham (2011)
Neuroendocrine and mucinous differentiation in signet ring cell carcinoma of the stomach: evidence for a common cell of origin in composite tumors.Human pathology, 42 10
Jing Huang, Yi Zhou, Xin-bo Zhao, Hongtu Zhang, Xinghua Yuan, Jinwan Wang (2012)
Primary small cell carcinoma of the stomach: An experience of two decades (1990–2011) in a Chinese cancer instituteJournal of Surgical Oncology, 106
T. Terada, H. Maruo (2011)
Simultaneous large cell neuroendocrine carcinoma and adenocarcinoma of the stomach.World journal of gastroenterology, 17 43
Les cellules argentaffines dans les tumeurs intesti - nales
M. Kitagawa, D. Ichikawa, S. Komatsu, K. Okamoto, A. Shiozaki, H. Fujiwara, Y. Murayama, Y. Kuriu, H. Ikoma, M. Nakanishi, T. Ochiai, Y. Kokuba, T. Sonoyama, E. Otsuji (2013)
Evaluation of lymph node metastasis in patients with gastric cancer: a comparison of the directionality of lymph node metastasis and the total number of metastatic lymph nodesSurgery Today, 43
Nimmi Kapoor, J. Shamonki, M. Sim, C. Chung, A. Giuliano (2013)
Impact of Multifocality and Lymph Node Metastasis on the Prognosis and Management of Microinvasive Breast CancerAnnals of Surgical Oncology, 20
M. Milione, P. Maisonneuve, F. Spada, A. Pellegrinelli, P. Spaggiari, L. Albarello, E. Pisa, M. Barberis, A. Vanoli, R. Buzzoni, S. Pusceddu, L. Concas, F. Sessa, E. Solcia, C. Capella, N. Fazio, S. Rosa (2016)
The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic CategoriesNeuroendocrinology, 104
M. Scardoni, E. Vittoria, M. Volante, B. Rusev, S. Bersani, A. Mafficini, M. Gottardi, V. Giandomenico, G. Malleo, G. Butturini, S. Cingarlini, M. Fassan, A. Scarpa (2014)
Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two ComponentsNeuroendocrinology, 100
U. Pape, U. Berndt, J. Müller-Nordhorn, M. Böhmig, S. Roll, M. Koch, S. Willich, B. Wiedenmann (2008)
Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours.Endocrine-related cancer, 15 4
PhD MD (2010)
7th Edition of the AJCC Cancer Staging Manual: StomachAnnals of Surgical Oncology, 17
Y. Boo, Sung-Soo Park, Jong-Han Kim, Y. Mok, Seong‐Joo Kim, Chong‐Suk Kim (2007)
Gastric neuroendocrine carcinoma: Clinicopathologic review and immunohistochemical study of E‐cadherin and Ki‐67 as prognostic markersJournal of Surgical Oncology, 95
Y. Nakayama, A. Higure, K. Shibao, Nagahiro Sato, Nobutaka Matayoshi, K. Yamaguchi (2012)
Synchronous occurrence of early neuroendocrine carcinoma and tubular adenocarcinoma in the stomachClinical Journal of Gastroenterology, 5
K. Bakkelund, R. Fossmark, I. Nordrum, H. Waldum (2006)
Signet Ring Cells in Gastric Carcinomas Are Derived from Neuroendocrine CellsJournal of Histochemistry & Cytochemistry, 54
E. Ilett, S. Langer, I. Olsen, B. Federspiel, A. Kjær, U. Knigge (2015)
Neuroendocrine Carcinomas of the Gastroenteropancreatic System: A Comprehensive ReviewDiagnostics, 5
Hirokazu Fukui, Hirokazu Fukui, M. Takada, Tsutomu Chiba, R. Kashiwagi, M. Sakane, F. Tabata, Yoshikazu Kuroda, Yoshihiko Ueda, Hitoshi Kawamata, J. Imura, Takahiro Fujimori (2001)
Concurrent occurrence of gastric adenocarcinoma and duodenal neuroendocrine cell carcinoma: a composite tumour or collision tumours ?Gut, 48
Soo-Hong Kim, B. Park, H. Kim, Jae Kim (2017)
Synchronous quintuple primary gastrointestinal tract malignancies: Case report.World journal of gastroenterology, 23 1
G. Rindi, G. Petrone, F. Inzani (2014)
The 2010 WHO Classification of Digestive Neuroendocrine Neoplasms: a Critical Appraisal four years after Its IntroductionEndocrine Pathology, 25
J. Park, M. Ryu, Y. Park, Hye Park, B. Ryoo, M. Kim, J. Yook, B. Kim, Yoon-Koo Kang (2014)
Prognostic significance of neuroendocrine components in gastric carcinomas.European journal of cancer, 50 16
N. Fazio, M. Milione (2016)
Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications.Cancer treatment reviews, 50
M. Sasako, M. Saka, T. Fukagawa, H. Katai, T. Sano (2007)
Surgical Treatment of Advanced Gastric Cancer: Japanese PerspectiveDigestive Surgery, 24
Shi‐Xu Jiang, T. Mikami, Atsuko Umezawa, M. Saegusa, T. Kameya, I. Okayasu (2006)
Gastric Large Cell Neuroendocrine Carcinomas: A Distinct Clinicopathologic EntityThe American Journal of Surgical Pathology, 30
M. Ishida, S. Sekine, T. Fukagawa, M. Ohashi, S. Morita, H. Taniguchi, H. Katai, H. Tsuda, R. Kushima (2013)
Neuroendocrine Carcinoma of the Stomach: Morphologic and Immunohistochemical Characteristics and PrognosisThe American Journal of Surgical Pathology, 37
K. Lewin (1987)
Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas.The American journal of surgical pathology, 11 Suppl 1
F. Cuttitta, D. Carney, J. Mulshine, T. Moody, J. Fedorko, A. Fischler, J. Minna (1985)
Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancerNature, 316
D. Furlan, R. Cerutti, Anna Genasetti, G. Pelosi, S. Uccella, S. Rosa, C. Capella (2003)
Microallelotyping Defines the Monoclonal or the Polyclonal Origin of Mixed and Collision Endocrine-Exocrine Tumors of the GutLaboratory Investigation, 83
H. Sorbye, E. Baudin, A. Perren (2018)
The Problem of High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Beyond.Endocrinology and metabolism clinics of North America, 47 3
Tingting Zhang, D. Su, Z. Mao, Xiao-chuan Guo, Li-jie Wang, L. Bai (2015)
Prognostic role of neuroendocrine cell differentiation in human gastric carcinoma.International journal of clinical and experimental medicine, 8 5
Helen Young, N. Carr, B. Green, C. Tilley, V. Bhargava, N. Pearce (2013)
Accuracy of visual assessments of proliferation indices in gastroenteropancreatic neuroendocrine tumoursJournal of Clinical Pathology, 66
Japanese Association (1998)
Japanese Classification of Gastric Carcinoma – 2nd English Edition –Gastric Cancer, 1
B. Kim, Y. Park, J. Yook, Byung-Sik Kim (2017)
Comparison of relapse-free survival in gastric neuroendocrine carcinoma (WHO grade 3) and gastric carcinomaTherapeutic Advances in Gastroenterology, 10
G. Rindi, C. Azzoni, S. Rosa, Catherine Klersy, D. Paolotti, S. Rappel, M. Stolte, Carlo Capella, C. Bordi, Enrico Solcia (1999)
ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis.Gastroenterology, 116 3
A. Michalinos, A. Constantinidou, M. Kontos (2015)
Gastric Collision Tumors: An Insight into Their Origin and Clinical SignificanceGastroenterology Research and Practice, 2015
Hindawi Journal of Oncology Volume 2019, Article ID 3671268, 12 pages https://doi.org/10.1155/2019/3671268 Research Article The Significant Influence of the Neuroendocrine Component on the Survival of Patients with Gastric Carcinoma Characterized by Coexisting Exocrine and Neuroendocrine Components 1 2 1 3 Hu Ren , Su-Sheng Shi, Nian-Chang Wang, Xing Wang, 1 1 Ying-Tai Chen , and Dong-Bing Zhao Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, , China Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, , China Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, , China Correspondence should be addressed to Ying-Tai Chen; yingtai.chen@hotmail.com and Dong-Bing Zhao; dbzhao2003@sina.com Received 4 August 2018; Revised 30 January 2019; Accepted 18 February 2019; Published 12 March 2019 Academic Editor: Reza Izadpanah Copyright © 2019 Hu Ren et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Gastric adenocarcinoma patients with a neuroendocrine (NE) component are frequently observed in routine practice. Several previous studies have investigated the influence of a NE component on the survival of these patients; however, the results were inconsistent. Methods. We retrospectively investigated a consecutive series of 95 gastric adenocarcinoma patients with a NE component and 190 gastric adenocarcinoma patients without a NE component. We adopted 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% as the cut-off proportions of the NE component, respectively, and analyzed the patients’ overall survival according to the proportion of the NE component. Results. eTh 1-, 3-, and 5-year actual survival rates of the patients with a NE component were 90.1%, 72.3%, and 67.2%, respectively, and for those without a NE component 94.2%, 79.3%, and 75.7%, respectively. The multivariate analysis showed that the patients with NE components>70% (HR:2.156;95% CI:1.011, 4.597; p=.)and>90% (HR: 2.476; 95% CI: 1.088, 5.634; p=.) had significantly worse survival than those without a NE component. Only the diameter of tumors (>4.64 cm)(HR: 2.585;95% CI:1.112, 6.006; p=.) and pN3 (HR:2.953; 95% CI:1.051,8.293; p=.) were independently associated with worse overall survival for gastric adenocarcinoma patients with a NE component (all p<.). Conclusion.Gastric adenocarcinoma patients with a NE component>70% and>90% have significantly worse survival than those without a NE component. Only the diameter of tumors and the number of metastatic lymph nodes are independent prognostic factors for gastric adenocarcinoma patients with a NE component. 1. Introduction gastroenterologists, and pathologists [2]. The spectrum of the carcinoma shows mixed divergent differentiation along the The first description of gastrointestinal tumors with exocrine exocrine and NE systems, and these two components express and neuroendocrine (NE) components was published by variable proportions ranging from 1% to 99% [3]. Cordier in 1924 [1]. Since then, several cases have been The prognostic significance of the NE component reported with many different names including compos- remains controversial in gastric adenocarcinoma (GAC) ite carcinoid, mucin-producing carcinoid, argentan ffi cell patients with a NE component. In 1987 [4], Lewin defined the adenocarcinoma, goblet cell carcinoid, adenocarcinoid, and criteria for determining the extent of the NE component in small cell undifferentiated carcinoma. These different names mixed adenoneuroendocrine carcinomas (MANEC) as 30%, led to considerable confusion among clinicians, surgeons, which incidentally is the same as that currently used [3]. The 2 Journal of Oncology cut-off proportion of 30%, however, is somewhat arbitrary, staining with one of three NE markers from Beijing Zhong- because not enough data are available for demonstrating shan Golden Bridge Biotechnology Co. Ltd. (ZsBio), China the prognostic significance of the NE component [5]. Chen (synaptophysin SYN (cat. no. ZA-0506), chromogranin A CgA (cat. no. ZM-0076), and CD56 (cat. no. ZM-0057)). et al. [3] found that a high NE component (>50%) in primary tumors was associated with poor prognosis. Park We used the archived specimens for IHC analysis with the et al. [5] suggested that a NE component (≥10%) is an enhanced labeled polymer system (ELPS) and divided those independent factor for poor prognosis. But it remains unclear results into different grades according to the number of how the NE phenotype may confer adverse prognosis; even positive cells and the intensity of positive staining. The Ki- the NE expression might promote tumor cells’ growth via an 67 index was assessed in areas of highest nuclear labeling, the autocrine or paracrine loop [6, 7]. so-called hot spots, by the manual counting of 500-2000 cells Our study aimed to provide a general understanding of [10, 11]. And the mitotic index per 10 high power elds fi (HPF) the prognostic influence of the NE components on GAC with =2 mm was counted in 50 high power elds fi including hot a NE component. To the best of our knowledge, this cohort is spots [11]. The scoring system for IHC was modified and used one of the largest to date in the literature for the patients with with permission by the Clinical and Laboratory Standards gastric carcinoma (GC) with exocrine and NE components. Institute (CLSI), document I/LA28-A2 [8]. The pathologic criteria for the NE component according to the 2010 WHO classification were as follows: (1) organoid 2. Materials and Methods architectures such as solid nests, sheets, broad trabeculae, .. Patients. A total of 95 patients with GAC with a or rosette formation; (2) nuclear features manifested by hyperchromatic nuclei with n fi ely to coarsely granular, but NE component (GAC with neuroendocrine differentiation (NED), MANEC, and neuroendocrine carcinoma (NEC)) evenly distributed, chromatin; and (3) cytoplasmic features who underwent radical gastrectomy with D2 lymphadenec- with a scant to moderate amount of slightly eosinophilic, tomy at the China National Cancer Center between February n fi ely granular cytoplasm and indistinct cellular mem- 2011 and January 2016 were identified and included in the branes [5, 9]. And the scattered positive NE cells identi- study. To evaluate the prognostic significance of the NE fied in the GAC area qualified for this definition. Patients component, we selected double GAC patients without a NE with total well differentiated NET were excluded in our component during the same period according to the baseline study. After evaluating the proportion of the NE compo- clinicopathological factors in the group of GAC with a NE component. nent, we analyzed its prognostic influence on GAC with The study inclusion criteria were as follows: (1) the diag- the NE component separately by setting 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% as the thresholds, nosis of GAC patients with a NE component was confirmed by two pathologists, using the 2010 World Health Orga- respectively. nization (WHO) classification of gastric neuroendocrine neoplasms (NENs) for histopathologic evaluation [9]; (2) the .. Surgical Procedures and Follow-Up. All the patients patients underwent gastrectomy with D2 lymphadenectomy systematically underwent gastrectomy with standard D2 lym- and R0 resection, which was determined by no macroscopic phadenectomy performed by experienced surgeons following or microscopic residual carcinoma; and (3) all the data of the the Japanese Gastric Cancer Association (JGCA) guidelines patients were available in terms of medical history, record [12]. The surgical gastrectomy procedures (subtotal or total of surgery, pathological report, and follow-up. The exclusion gastrectomy or combined organ resection) were chosen aeft r criteria were as follows: (1) patients had distant metastasis; (2) discussion by the multidisciplinary team based largely on patients underwent palliative surgery; (3) patients had a total the GC treatment guidelines of the JGCA. The patients well differentiated neuroendocrine tumor (NET) (G1, G2, were examined on a weekly basis during the period of and G3); (4) patients died from other reasons of unexpected treatment. After completion of the treatment, they were outcomes; (5) patients had suffered from other malignancies followed up every 3 or 6 months until death. The follow- before GC; or (6) patients were lost to follow-up. up analysis was carried out on their postoperative treatment All the patients included in this study were examined information, time to recurrence, and time of death. The with upper gastrointestinal tract endoscopy and enhanced long-term prognostic data were obtained from the patients’ CT/MRI scanning to avoid possible missing lesions. Their clinical records or contact with the patients’ relatives by clinical information was obtained from their medical records telephone. in each case. All the study procedures were approved by the Institutional Review Board at the China National Cancer .. Statistics. The following clinical and pathological data Center. were collected: demographic information (gender and age), .. Definition and Evaluation of NE Component. The patho- clinical and pathological tumor features (location, diameter, logical conditions of all the patients were reviewed individ- Bormann’s classification, the Lauren classification, and classi- ually by two pathologists to redefine the proportion of the fication of pT stages, pN stages, and pTNM stages according NE component with reference to the area of tumor cells. to the 7th edition of the American Joint Committee on Can- In the primary tumors, the NE component was conrfi med cer/Union Internationale Contre le Cancer (AJCC/UICC) for with morphology and positive immunohistochemical (IHC) GC [13]), proportion of the NE component, NE markers Journal of Oncology 3 (SYN, CgA, and CD56), mitotic gur fi es and Ki-67 which only The mean Ki-67 index was 56.21%. Table 1 also summarized refer to the NE component in this carcinoma, neoadjuvant the information about the Lauren type, neoadjuvant therapy, therapy, and adjuvant chemotherapy. adjuvant therapy, and relapse or metastasis. As the primary endpoint, overall survival (OS) was den fi ed as the time from surgery to death or of last follow- .. IHC Staining Pattern of GAC with a NE Component. For up (updated on March 1, 2018). The dates of death from any the IHC staining pattern of these 95 cases, all the tumors were cause were obtained from the medical records and the China positive for at least 1 of three conventional NE markers: SYN, National Citizen Identity Information Center. The survival CgA, and CD56. The immune positivity of each NE marker curves were analyzed with the Kaplan–Meier method and was listedin Table 1. SYN was foundto be the most sensitive their differences were estimated with a log-rank test. The marker which was positive in 87 cases (87/95, 91.58%), univariate and multivariate Cox proportional hazard analysis followed by CgA and CD56 which were positive in 70 cases was performed to evaluate the prognostic significance for (70/95, 73.68%) and 42 cases (42/76, 53.85%), respectively. the OS, with the hazard ratio (HR) and 95% confidence The expression for all three markers was recognized in 22 interval (95% CI) generated at the same time. Some mixed cases (23.16%), but 2 lesions expressed SYN and/or CgA factors, such as gender, age, and adjuvant therapy (yes or no), (97.89%). There were significant differences in the expressions which may influence the survival in the univariate analysis, of these IHC markers (p<.). SYN was the most sensitive were also included in the Cox proportional hazard model marker of the NE component, while CD56 was the most (multivariate analysis). A p value<0.05 was considered to insensitive marker. indicate statistically significant differences for all tests. All the tests were 2-sided and were performed using SPSS 25.0 (SPSS .. Prognostic Significance of NE Component in GAC. To Inc., Chicago, IL, USA). validate the prognostic significance of the NE component, we compared the prognoses of GAC with and without 3. Results and Discussion a NE component first. During the follow-up period, in the group of GAC with a NE component, 49 patients .. Clinicopathological Features. A total of 95 consecutive (51.58%) had recurrence or metastasis, while, in the group GAC patients with a NE component were identified, and 190 of GAC without a NE component, 53 (27.89%) patients GAC ones without a NE component were included in the did. The final follow-up results showed that the 1-, 3-, and study. We were able to categorize the patients with GAC with a 5-year actuarial survival rates of the patients with a NE NE component into three groups according to the 2010 WHO component were 90.1%, 72.3%, and 67.2%, respectively, and classification of NENs of the digestive system: (1) GAC with for the patients without a NE component 94.2%, 79.3%, NED (0<NE<30%) (n=32), (2) MANEC (30%≤NE≤70%) and 75.7% (Table 3). Recurrence or metastasis was more (n=29), and (3) NEC (70%<NE<100%) (n=34). There was frequently identified in the patients with a NE component no significant difference in gender, age, tumor diameter, (p<.). However, GAC patients with a NE component tumor location, pathological status, SYN, CgA, CD56, and (without well differentiated NET) had slightly worse survival adjuvant therapy among these three groups, and all the than GAC patients without a NE component, rather than clinicopathological features were not significantly different statistically significant difference (p=. )(Figure 2and between GAC groups with and without a NE component Table 2). (Table 1). The representative pathologic images of each group were shown in Figure 1. To explore the prognostic significance of the proportion These 95 GAC patients with a NE component, including of the NE component in GAC patients with a NE component, 82 male and13 female ones, hada median age of61.37 we divided the patients with GAC with a NE component (range: 39–79 years). According to the surgical records, the into three groups according to the 2010 WHO classification primary tumor preferred more to locate in the upper part of of NENs of the digestive system: (1) GAC with NED, (2) the stomach (54.74%), while 25 lesions were located in the MANEC, and (3) NEC. The Kaplan–Meier survival curves lower part of the stomach (26.31%), and 18 lesions were in of the four groups were shown in Figure 3(a) (p=.). As the middle of the stomach (18.95%). The median diameter showninTable 3, only NECpatients had worseoutcome of the primary tumors was 4.64 cm. According to the 7th compared with GAC ones without a NE component in AJCC/GC TNM staging system for GC [13], the postoperative the univariate analysis (p=.). Then, we included some pathological results showed that only 20 patients (21.05%) factors (age, tumor location, tumor diameter, and pT and pN had tumors confined in the mucosa, submucosa, or muscu- stage) which may aec ff t the survival of all GAC patients in laris propria (pT1 or pT2), while 75 patients (78.95%) had the univariate and multivariate analysis (the data were not ones that invaded beyond the muscularis propria (pT3 or shown). The result showed that the patients with NEC still pT4). The status of the metastatic lymph nodes showed that had significantly worse survival than those with GAC without only 29 patients (30.53%) were pN0 and 66 (69.47%) were aNEcomponent (p=.). pN+. u Th s, most of the patients (81/95, 85.26%) had advanced Further,weadopted10%,20%,30%,40%,50%,60%,70%, diseases in the final pTNM stage. Most of the cases showed 80%, and 90% of the NE component as cut-off proportions, the frequent mitoses with an average of 37.71/2 mm (range: 3 respectively, and analyzed the patients’ OS according to the proportion of the NE component shown. As shown in Table 3 to 180/2 mm ). And most of the cases (82/87) presented a high Ki-67 index (>20%), while only 5 presented a low one (≤20%). and Figure 3, the GAC patients with NE components>70% 4 Journal of Oncology Table 1: Clinicopathological features for all patients. GAC with NE component GAC with GAC without MANEC NEC Variables p value NED Total NE component (30≤NE≤70%) (70<NE<100%) (0<NE<30%) Gender Male 28 24 30 82 142 0.247 Female 4 5 4 13 48 Age (years) ≤60 15 12 16 43 100 0.241 >60 17 17 18 52 90 Location Upper 19 15 18 52 86 0.127 Middle 2 8 8 18 31 Lower 11 6 8 25 73 Curvature Lesser 16 8 14 38 91 0.194 Greater 1 3 5 9 37 Diameter (cm) (mean) 4.82 4.09 5.16 4.64 4.78 Lauren type Intestinal 15 11 4 30 63 0.234 Diffuse 4 7 5 16 59 Mixed 11 8 3 22 47 pT stage T1 3 5 1 9 27 T2 5 4 2 11 20 0.062 T3 17 14 26 57 85 T4 7 6 5 18 58 pN stage N0 11 8 10 29 59 N1 5 7 5 17 46 0.462 N2 6 2 9 17 36 N3 10 12 10 32 49 pTNM stage I 5 7 2 14 35 0.717 II 11 6 12 29 58 III 16 16 20 52 97 Synaptophysin Negative 6 2 0 8 N/A 1+ 26 15 14 55 2+ 0 12 20 32 Chromogranin Negative 6 9 10 25 N/A 1+ 26 14 14 54 2+ 0 6 10 16 CD56 Negative 19 11 12 42 1+ 6 4 5 15 N/A 2+ 1 4 3 8 3+ 0 5 6 11 Mitotic index (2 mm ) 35.67 29.50 49.38 37.71 (mean) Ki-67 (%) 56.00 55.44 57.70 56.21 (mean) Neoadjuvant No 31 25 34 90 179 therapy 0.856 Yes 1 1 3 5 11 Adjuvant No 10 6 15 31 45 therapy 0.074 Yes 18 22 18 59 141 Follow-up (month) (mean) 43.6 38.2 40.1 40.8 45.7 N/A: not applicable. eTh scoring system for IHC modified and used with permission by the Clinical and Laboratory Standards Institute (CLSI), document I/LA28-A2 [8]. Journal of Oncology 5 (a) (b) (c) (d) Figure 1: The representative pathologic images of each group (H&E X100). (a) is an emblematic image in the GAC group without a NE component; (b) is an emblematic image in the GAC group with NED; (c) is an emblematic image in the MANEC group; (d) is an emblematic image in the NEC group. and>90% had significantly worse survival than GAC ones (56.31 months), this did not reach statistical significance without a NE component in the univariate and multivariate (Figure 3(d)) (p=. ). Other factors, such as gender, age, analysis. pT stage, pTNM stage, Ki-67, mitosis, and adjuvant ther- apy, were not significant predictors of survival (all p>.) (Table 4). .. Univariate and Multivariate Analysis for GAC Patients In the multivariate analysis, only the diameter of the with a NE Component. All the patients’ follow-up informa- tumors (>4.64 cm)(HR:2.585; 95% CI: 1.112,6.006; p=.) tion was available, with the median follow-up period of 44.07 and pN3 (HR: 2.953; 95% CI: 1.051, 8.293;p=.) were inde- months (range from 2 to 84 months) for all of them. We pendently associated with worse OS (all p<.)(Table 4). evaluated some possible factors associated with OS in the Moreover, there was no significant difference in the predictors GAC patients with a NE component. The univariate analysis of survival among pN0, pN1, and pN2 (Figure 4). showed that the lower location in the stomach (hazard ratio (HR): 0.210; 95% cond fi ence interval (CI): 0.049, 0.897; 4. Discussion p=.), the diameter of the primary tumor (>4.64 cm) (HR: 3.076; 95% CI: 1.356, 6.976; p=.), and pN3 (HR: Only a few reports have evaluated the prognostic signicfi ance 3.359; 95% CI: 1.198, 9.417; p=.)were the signicfi ant of the NE component of GC; even the coexistence of the predictors of survival. While the patients with a NE com- NE component and adenocarcinoma is frequently observed ponent 0<NE≤70% had longer medium survival time (64.69 [6, 14–16]. Several previous studies have proved that the months) than ones with a NE component 70%<NE<100% well differentiated NET had better survival than the poorly 6 Journal of Oncology Table 2: Overall survival rates of the two groups. OS rate 1-year, % (95% CI) 2-year, % (95% CI) 3-year, % (95% CI) 4-year, % (95% CI) 5-year, % (95% CI) GAC with NE component 90.1 (83.6,96.6) 82.5 (74.3,90.7) 72.3 (61.7,82.9) 70.1 (58.9,81.3) 67.2 (55.2,79.2) GAC without NE component 94.2 (90.9,97.5) 86.3 (81.4,91.2) 79.3 (73.2,85.4) 77.8 (71.5,84.1) 75.7 (69.0,82.4) Table 3: Cox regression model for the NE component. Univariate analysis Multivariate analysis NE component Number HR (95% CI) p value HR (95% CI) p value No 190 1 (reference) 1 (reference) Yes 95 1.534 (0.935, 2.518) 0.090 1.292 (0.771, 2.164) 0.330 No 190 1 (reference) 1 (reference) GC with NED (0<NE<30%) 32 1.358 (0.661, 2.791) 0.404 1.224 (0.588, 2.549) 0.590 MANEC (30%≤NE≤70%) 29 1.209 (0.543, 2.695) 0.642 0.897 (0.392, 2.054) 0.797 NEC (70%<NE<100%) 34 2.318 (1.128, 4.766) 0.022 2.155 (1.011, 4.593) 0.047 No 190 1 (reference) GC with NE component 0<NE≤10% 30 1.429 (0.696, 2.938) 0.331 GC with NE component 10%<NE<100% 65 1.601 (0.0899, 2.849) 0.110 No 190 1 (reference) GC with NE component 0<NE≤20% 32 1.358 (0.661, 2.791) 0.405 GC with NE component 20%<NE<100% 63 1.656 (0.930, 2.946) 0.086 No 190 1 (reference) 1 (reference) GC with NE component 0<NE≤30% 42 1.131 (0.568, 2.256) 0.726 1.067 (0.530, 2.151) 0.855 GC with NE component 30%<NE<100% 53 2.013 (1.116, 3.633) 0.020 1.524 (0.816, 2.847) 0.186 No 190 1 (reference) 1 (reference) GC with NE component 0<NE≤40% 52 1.311 (0.716, 2.402) 0.380 1.172 (0.634, 2.167) 0.614 GC with NE component 40%<NE<100% 43 1.959 (1.008, 3.806) 0.047 1.513 (0.749, 3.059) 0.249 No 190 1 (reference) GC with NE component 0<NE≤50% 54 1.379 (0.764, 2.487) 0.286 GC with NE component 50%<NE<100% 41 1.847 (0.927, 3.683) 0.081 No 190 1 (reference) GC with NE component 0<NE≤60% 58 1.169 (0.769, 2.435) 0.286 GC with NE component 60%<NE<100% 37 1.955 (0.951, 4.018) 0.068 No 190 1 (reference) 1 (reference) GC with NE component 0<NE≤70% 61 1.289 (0.725, 2.294) 0.388 1.060 (0.585, 1.920) 0.848 GC with NE component 70%<NE<100% 34 2.318 (1.128, 4.765) 0.022 2.156 (1.011, 4.597) 0.047 No 190 1 (reference) GC with NE component 0<NE≤80% 65 1.368 (0.778, 2.404) 0.276 GC with NE component 80%<NE<100% 30 2.070 (0.971, 4.412) 0.059 No 190 1 (reference) 1 (reference) GC with NE component 0<NE≤90% 67 1.334 (0.759, 2.344) 0.317 1.061 (0.592, 1.902) 0.842 GC with NE component 90%<NE<100% 28 2.253 (1.057, 4.802) 0.035 2.476 (1.088, 5.634) 0.031 differentiated NEC [17]. In this study, we included the poorly GAC ones without a NE component. The recent 2010 WHO differentiated NEC to compare with other malignant tumors, classification classifies NENs of the stomach into three cat- such as GC,GAC with NED, andMANEC.Tothe best of egories according to the proportion of the NE component: our knowledge, this is one of the largest studies to provide a MANEC (30%≤NE≤70%), a neuroendocrine tumor (NET) general understanding of the prognostic influence of the NE or NEC (NE>70%), and GC with NED (0<NE<30%) [9]. component in patients with GAC. Several studies reported that the cut-off proportion of 30%, The most notable finding of our study was that GAC however, was somewhat arbitrary, because not enough data patients with a NE component >70% (NEC) and with a are available for demonstrating the prognostic significance of the NE component [5]. The previous observation reported NE component>90% had significantly worse survival than Journal of Oncology 7 Table 4: Univariate and multivariate analyses for patients with a NE component. Univariate analysis Multivariate analysis Variables HR (95% CI) p value HR (95% CI) p value Gender M 1 (reference) F 0.828 (0.248, 2.770) 0.760 Age ≤60 1 (reference) >60 2.310 (0.964, 5.536) 0.061 Location Upper 1 (reference) 1 (reference) Middle 0.278 (0.065, 1.190) 0.084 0.338 (0.074, 1.551) 0.163 Lower 0.210 (0.049, 0.897) 0.035 0.391 (0.083, 1.848) 0.236 Curvature Lesser 1 (reference) Greater 1.703 (0.349, 8.321) 0.511 Diameter ≤4.64 1 (reference) 1 (reference) >4.64 3.076 (1.356, 6.976) 0.007 2.585 (1.112, 6.006) 0.027 Lauren type Intestinal 1 (reference) Diffuse 0.941 (0.289, 3.068) 0.920 Mixed 1.092 (0.406, 2.938) 0.861 pT stage 1 1 (reference) 2 0.619 (0.039, 9.922) 0.734 3 1.775 (0.233, 13.527) 0.580 4 3.297 (0.405, 26.867) 0.265 pN stage 0 1 (reference) 1 (reference) 1 0.934 (0.223, 3.915) 0.926 0.952 (0.226, 4.021) 0.947 2 0.827 (0.196, 3.486) 0.796 0.862 (0.200, 3.721) 0.842 3 3.359 (1.198, 9.417) 0.021 2.953 (1.051, 8.293) 0.040 pTNM stage I 1 (reference) II 2.023 (0.240, 17.041) 0.517 III 4.081 (0.541, 30.764) 0.172 NE component 0<NE≤70% 1 (reference) NE component 1.718 (0.756, 3.903) 0.196 70%<NE<100%/ Ki-67 (%) ≤56.21 1 (reference) >56.21 2.696 (0.834, 8.710) 0.097 Mitotic index ≤37.71 1 (reference) >37.71 1.887 (0.696, 5.118) 0.212 Adjuvant N 1 (reference) therapy Y 1.245 (0.449, 3.452) 0.674 that there was no significant difference in survival between (p=. ), while the result in the present study showed that NEC and MANEC [18, 19], although this result needs to be GAC patients with a NE component (0<NE≤70%) (GAC with verified in other independent patient groups. NED and MANEC) had no significantly different survival Firstly, we evaluated the influence of the NE component compared to GAC ones without a NE component (p=. ). between GAC patients with and without a NE component. Then we analyzed the patients’ outcomes according to the Several studies have reported that patients with gastric NEC dieff rent cut-off proportions of the NE component. Several had worse OS than those with GAC [6, 19]. Similarly, in studies have reported that a higher NE component in primary our data, the OS rate of the patients with gastric NEC tumors predicted poor prognosis in terms of GAC with a was poorer than that of ones with GAC without a NE NE component [3, 5, 6]. Jiang et al. [6] suggested that when component. For all GAC patients with a NE component >20% SYN/CgA positivity was set, the prognosis of large (without well differentiated NET) in our study, the OS rates of cell neuroendocrine carcinomas (LCNEC) was significantly the GAC groups with and without a NE component showed worse than that of GC with NED. But when the threshold slight difference, instead of statistically significant difference for LCNEC was set to >50%, >40%, or >30% CgA/SYN 8 Journal of Oncology set 70% of the NE component as the threshold to analyze 1.0 the inu fl ence of the proportion of the NE component in GAC patients with a NE component. Possibly due to the GAC without NE component 0.8 limited sample sizes, there was no significant difference in survival between patients with a smaller NE component (0<NE≤70%) and a larger NE component (70%<NE<100%) 0.6 (p=. ). GAC with NE component In this research, our data indicated that the prognosis of the GAC patients with a NE component and the number of 0.4 metastatic lymph nodes≤ 6 (pN1 and pN2) were similar to those of ones without metastatic lymph node involved (pN0), p = 0.087 0.2 which was significantly better than that of the patients with the number of metastatic lymph nodes exceeding 6 (pN3). As we have known, nodal involvement is one of the most 0.0 crucial indicators of prognosis in patients with resectable 0 20 40 60 80 100 malignant gastric tumors following curative surgery [24]. The Time (months) number of metastatic lymph nodes is a powerful prognostic Figure 2: Overall survival of all the patients in the two groups. factor in several malignant tumor types such as carcinoma of the digestive system and the breast [25, 26]. The classi- fication of metastatic lymph nodes in gastric NEC is still positivity, the survival difference was not significant between under extensive evaluation [27]. Accordingly, we divided the 2 groups. Park et al. [5] suggested that NEC, MANEC, all patients into four groups (pN0, pN1, pN2, and pN3) according to the 7th AJCC/GC TNM staging system for GC and GC with NED (>10% NE) showed poorer outcomes than GC with NED (<10% NE) or without a NE component. [13]. However, it was easy to find that there was no significant Generally, it has been suggested that angioinvasion, clinicopathological type, mitosis, and Ki-67 index are the dieff rence in the survival rates among NEC, MANEC, and GC with 10–30% of NED in Park’s study [20]. Furthermore, predictors of tumor malignancy and patients’ outcome [28]. However, in our study, we found from the Cox proportional Chen et al. [3] proposed that a high NE component (>50%) in the primary tumors was associated with poor prognosis. hazard model assessment that Ki-67, mitosis, and adjuvant But their study was a small sample test, because only 21 therapy were not signicfi ant factors for prognosis of GAC with a NE component (p>.), which is inconsistent with patients were included. While the mechanisms underlying this phenomenon remained unclear, a possible explanation previous studies [19, 29]. Milione et al. [30] and Boo et was that the NE component might actually upregulate the al. [31] reported that the Ki-67 labeling index was related to gastric NEC recurrence and prognosis. Xie et al. [19] expression of the vascular endothelial growth factor (VEGF) and affect the incidence of lymph node metastasis to promote revealed signicfi antly reduced postrecurrence survival (PRS) neoangiogenesis [3, 21, 22]. As such, we adopted 10%, 20%, for the high Ki-67 (≥57.5%) labeling index group compared with the low Ki-67 labeling index group and that the Ki- 30%, 40%, 50%, 60%, 70%, 80%, and 90% of the NE compo- nent as thresholds, respectively, and compared the patients’ 67 labeling index was an independent factor influencing the PRS of gastric NEC. Similarly, in our data, we found patients OS with that of the GAC patients without a NE component. When the proportion of the NE component was>70% and with the high Ki-67 (>56.21%) index group had slightly >90%, the patients had worse prognosis than GAC ones poorer survival than the low Ki-67 index group, rather than statistically significant difference ( p=. ). Moreover, without a NE component. And in our research, there were only 6 GAC patients with a NE component (70%<NE≤90%), according to the stratified analysis, PRS in the gastric which may have influenced the result when we adopted 80% NEC group was similar between patients who had received of the NE component as the threshold. chemotherapy and those who had not [19]. Kubota et al. Finally, in the current research, we observed that the [16] found no beneficial effect of adjuvant chemotherapy for gastric NEC while Huang et al. [32] disagreed with them. diameter of the tumors (≥4.64 cm) and pN3 were indepen- dently associated with worse OS for the GAC patients with One potential explanation for this conflicting result is that a NE component, which agreed with the previous reports optimal therapy for gastric NEC remains to be established yet [33]. [19]. Park et al. [5] stated that, in the univariate analysis, larger tumor size (>4 cm) and advanced pTNM stage group Few studies in the literature have reported the genetic were poor prognostic factors for both RFS and OS of GC. issue of these gastric carcinomas and most have described Ishida et al. found a better outcome of gastric NEC among dieff rent n fi dings and controversial data, thus leaving vari- patients with a larger tumor (>5.0 cm) (p<.)[18]. In our ous histogenetic hypotheses still unconfirmed. These gastric study, pT and pTNM stages were not significant predictors carcinomas may result from either the proliferation of stem of survival, which was different from the previous reports cells capable of differentiating along multiple cell lineages or [23]. This discrepancy might have been generated because of the simultaneous proliferation of multiple cell lineages [4, 34– 38]. Scardoni et al. [35] started a mutational survey on a series the fact that most of the patients were in the advanced stage of GAC in our study. According to the previous results, we of six gastroenteropancreatic MANEC to understand the Survival rate Journal of Oncology 9 1.0 1.0 GAC without NE component GAC without NE component 0.8 0.8 MANEC GC with NED GC with NE component 0.6 0.6 (30≤NE≤70%) (0<NE<30%) (70<NE<100%) NEC 0.4 0.4 (70<NE<100%) 0.2 0.2 p = 0.019 p = 0.126 0.0 0.0 0 20 40 60 80 100 020 40 60 80 100 Time (months) Time (months) (a) (b) 1.0 1.0 GAC without NE component 0.8 0.8 GAC with NE component 0<NE≤70% 0.6 0.6 GC with NE component (90%<NE<100%) GAC with NE component 0.4 0.4 70%<NE<100% p = 0.031 0.2 0.2 p = 0.190 0.0 0.0 0 20 40 60 80 100 0 20406080 100 Time (months) Time (months) (c) (d) Figure 3: Overall survival of the patients regrouped according to the proportion of the NE component. (a) All the cases were categorized into four groups: GAC without a NE component (n=190), GAC with NED 0<NE<30% (n=32), MANEC 30%≤NE≤70% (n=29), and NEC 70%<NE<100% (n=34); there was no significant difference in OS rates among these four groups ( p=.). We adopted 70% (b) and 90% (c) of the NE component as cut-off proportions, respectively; GAC patients with NE components >70% and>90% had significantly worse survival than GAC ones without a NE component (p=. and p=0.019, respectively). (d) We adopted 70% of the NE component as the cut- off proportions to compare the survival between two groups in GAC patients with a NE component, and there was no significant dieff rence between the two groups (p=. ). molecular basis of MANEC carcinogenesis and lineage com- studying clonality of a rectal endocrine-exocrine collision mitment. And the results showed that vfi e of six MANEC pre- tumor, found dieff rent origins of the tumor components. sented similar molecular profiles in both components, which Although rare, the since synchronous but remote gastric suggested an origin from a common progenitor cell of these tumors have been reported [40–42]. The origin of two carcinomas. Bakkelund et al. [39] found that a significant cells in these gastric carcinomas was controversial, and proportion of gastric cancers with signet ring cells occurring we are going to start some studies in these eld fi s in the in the oxyntic mucosa were of NE origin. At least a portion future. of these seemed to be derived from the enterochromaffin- Strengths and limitations should be considered when like (ECL) cells.Similarly,Bartley et al.[38] reported that the study results are interpreted. First, to the best of our the concordance of E-cadherin staining patterns between the knowledge, this is one of the largest studies to investigate signet ring and NE components may support the hypothesis the influence of the NE component on the survival of GAC that composite tumors arise from a common stem cell or patients. Second, the diagnosis of all patients was reviewed precursor cell with bidirectional or multidirectional differen- by two independent pathologists, which minimized potential tiation. However, it is noteworthy that Furlan et al. [36], while disease misclassification. The major limitation of our study Survival rate Survival rate Survival rate Survival rate 10 Journal of Oncology 1.0 1.0 0.8 0.8 0.6 0.6 0.4 p=0.012 0.4 p=0.001 0.2 0.2 0.0 0.0 0 20406080 100 0 20 40 60 80 100 Time (months) Time (months) pN stages pN stages N0 N2 N0, N1, and N2 N3 N1 N3 (a) (b) Figure 4: Overall survival of the patients in the GAC group with a NE component regrouped according to the pN stage. A statistically significant dieff rence in survival was observed between patients with less metastatic lymph nodes (pN0, pN1, and pN2) and those with the number of metastatic lymph nodes exceeding 6 (pN3) (p<0.001). er Th e was no significant dieff rence in the predictors of survival among pN0, pN1, and pN2 (p=0.964) (the figure is not shown) (Kaplan–Meier and log-rank test). was the lack of the data on long-term follow-up. Moreover, Acknowledgments the retrospective nature of this study can be associated This work was supported by the National Key R&D Program with selection bias as well as increased risks of differential of China (Grant No. 2017YFC0908300) and the Beijing Nova misclassification bias. In addition, all the patients analyzed Program (Grant No. xxjh2015A090). were from a single institution, so the n fi dings may not be generalizable for other settings. Also, while we had one of thelargest numbers of patients to date, thesample sizewas References modest; therefore chance cannot be ruled out for some of the [1] R. Cordier, “Les cellules argentaffines dans les tumeurs intesti- significant findings. nales,” Archives of Internal Medicine,vol.1,no.5,pp.59–63,1924. [2] S. La Rosa, A. Marando, F. Sessa, and C. Capella, “Mixed 5. Conclusions adenoneuroendocrine carcinomas (MANECs) of the gastroin- testinal tract: an update,” Cancers, vol.4,no. 1, pp.11–30,2012. In conclusion, our study found that GAC patients with a NE [3] M. Chen, Y. Kuo, Y. Yeh et al., “High neuroendocrine compo- component>70% (NEC) and with a NE component>90% nent is a factor for poor prognosis in gastrointestinal high-grade had significantly worse survival than GAC ones without malignant mixed adenoneuroendocrine neoplasms,” Journal of a NE component. And only the diameter of tumors and the Chinese Medical Association,vol.78,no.8,pp.454–459,2015. the number of metastatic lymph nodes were independent [4] K. Lewin, “Carcinoid tumors and the mixed (composite) prognostic factors for GAC patients with a NE component. glandular-endocrine cell carcinomas.,” e American Journal of However, the results in this study need to be further replicated Surgical Pathology,vol. 11,pp. 71–86,1987. in studies with larger sample sizes. [5] J. Y. Park, M. Ryu, Y. S. Park et al., “Prognostic significance of neuroendocrine components in gastric carcinomas,” European Data Availability Journal of Cancer, vol.50, no.16,pp.2802–2809, 2014. [6] S.-X.Jiang,T.Mikami,A.Umezawa,M.Saegusa,T.Kameya, The data used to support the findings of this study are and I. Okayasu, “Gastric large cell neuroendocrine carcinomas: available from the corresponding author upon request. a distinct clinicopathologic entity,” e American Journal of Surgical Pathology,vol. 30, no. 8,pp. 945–953, 2006. Conflicts of Interest [7] F.Cuttitta,D. N. Carney, J.Mulshine et al.,“Bombesin-like peptides can function as autocrine growth factors in human The authors declare that there are no conflicts of interest small-cell lung cancer,” Nature, vol.316,no.6031,pp.823–826, regarding the publication of this paper. [8] S. Hewitt, M. Robinowitz, S. Bogen et al., Quality Assurance for Design Control and Implementation of Immunohistochemistry Authors’ Contributions Assays: Approved Guideline, Clinical Lab Standards Institute, Hu Ren and Su-Sheng Shi contributed equally to this work. Wayne, PA, USA, 2011. Survival rate Survival rate Journal of Oncology 11 [9] F. Bosman, F. Carneiro, and R. H. Hruban, “WHO classification on the prognosis and management of microinvasive breast of tumours of the digestive system,” in Proceedings of the cancer,” Annals of Surgical Oncology, vol.20,no.8, pp. 2576– International Agency for Research on Cancer, p.417,Lyon, 2581, 2013. France, 2010. [26] M. Kitagawa,D.Ichikawa, S. Komatsuetal.,“Evaluation [10] H. T.Young, N. J. Carr,B. Green, C.Tilley, V. Bhargava, and N. of lymph nodemetastasisin patientswith gastric cancer: a Pearce, “Accuracy of visual assessments of proliferation indices comparison of the directionality of lymph node metastasis and in gastroenteropancreatic neuroendocrine tumours,” Journal of the total number of metastatic lymph nodes,” Surgery Today,vol. Clinical Pathology, vol.66,no.8,pp.700–704, 2013. 43, no. 2, pp. 130–135, 2013. [11] G. Rindi, G. Petrone, and F. Inzani, “eTh 2010 WHO classifica- [27] U.-F. Pape, U. Berndt, J. Muller ¨ -Nordhorn et al., “Prognostic tion of digestive neuroendocrine neoplasms: a critical appraisal factors of long-term outcome in gastroenteropancreatic neu- four years aeft r its introduction,” Endocrine Pathology,vol. 25, roendocrine tumours,” Endocrine-Related Cancer,vol.15,no. 4, no.2,pp.186–192, 2014. pp.1083–1097,2008. [12] A. Japanese Gastric Cancer, “Japanese classification of gastric [28] G.Rindi,C.Azzoni,S.LaRosaetal.,“ECLcelltumorandpoorly carcinoma - 2nd english edition,” Gastric Cancer,vol.1, no. 1, dieff rentiated endocrine carcinoma of the stomach: prognostic pp. 10–24, 1998. evaluation by pathological analysis,” Gastroenterology, vol. 116, [13] K. Washington, “7th edition of the AJCC cancer staging manual: no. 3, pp. 532–542, 1999. stomach,” Annals of Surgical Oncology,vol.17,no.12,pp. 3077– [29] N. Fazio and M. Milione, “Heterogeneity of grade 3 gastroen- 3079, 2010. teropancreatic neuroendocrine carcinomas: new insights and [14] H. L. Waldum, S. Aase, I. Kvetnoi et al., “Neuroendocrine treatment implications,” Cancer Treatment Reviews,vol. 50, pp. dieff rentiation in human gastric carcinoma,” Cancer,vol. 83, no. 61–67, 2016. 3, pp. 435–444, 1998. [30] M. Milione, P. Maisonneuve, F. Spada et al., “The clinico- [15] K. Nishikura, H. Watanabe, M. Iwafuchi, T. Fujiwara, K. pathologic heterogeneity of grade 3 gastroenteropancreatic Kojima, and Y. Ajioka, “Carcinogenesis of gastric endocrine cell neuroendocrine neoplasms: morphological differentiation and carcinoma: analysis of histopathology and p53 gene alteration,” proliferation identify different prognostic categories,” Neuroen- Gastric Cancer,vol.6,no.4,pp.203–209,2003. docrinology, vol.104,no. 1,pp. 85–93,2016. [16] T.Kubota, S.Ohyama, N.Hiki,S.Nunobe, N.Yamamoto, [31] Y.-J.Boo,S.-S. Park,J.-H.Kim, Y.-J.Mok, S.-J.Kim, and C.- and T. Yamaguchi, “Endocrine carcinoma of the stomach: S. Kim, “Gastric neuroendocrine carcinoma: clinicopathologic clinicopathological analysis of 27 surgically treated cases in a review and immunohistochemical study of E-cadherin and Ki- single institute,” Gastric Cancer, vol.15, no.3, pp. 323–330,2012. 67 as prognostic markers,” Journal of Surgical Oncology,vol. 95, [17] H. Sorbye, E. Baudin, and A. Perren, “eTh problem of high- no. 2, pp. 110–117, 2007. grade gastroenteropancreatic neuroendocrine neoplasms: well- [32] J. Huang, Y. Zhou, X. Zhao, H. Zhang, X. Yuan, and J. Wang, dieff rentiated neuroendocrine tumors, neuroendocrine carci- “Primary small cell carcinoma of the stomach: an experience of nomas, and beyond,” Endocrinology and Metabolism Clinics of two decades (1990-2011) in a Chinese cancer institute,” Journal North America,vol. 47, no.3, pp. 683–698, 2018. of Surgical Oncology, vol.106, no. 8, pp.994–998, 2012. [18] M. Ishida, S. Sekine, T. Fukagawa et al., “Neuroendocrine [33] E. Ilett, S. Langer, I. Olsen, B. Federspiel, A. Kjær, and U. Knigge, carcinoma of the stomach,” e American Journal of Surgical “Neuroendocrine carcinomas of the gastroenteropancreatic Pathology, vol. 37, no. 7, pp. 949–959, 2013. system: a comprehensive review,” Diagnostics, vol.5,no.2, pp. [19] J. Xie, J. Lu, J. Lin et al., “Different long-term oncologic 119–176, 2015. outcomes aer ft radical surgical resection for neuroendocrine [34] A. Michalinos, A. Constantinidou, and M. Kontos, “Gastric carcinoma and adenocarcinoma of the stomach,” Oncotarget , collision tumors: an insight into their origin and clinical vol. 8, no. 34, 2017. significance,” Gastroenterology Research and Practice,vol.2015, [20] B. S. Kim, Y. S. Park, J. H. Yook, and B. Kim, “Comparison Article ID 314158, 8 pages, 2015. of relapse-free survival in gastric neuroendocrine carcinoma (WHO grade 3) and gastric carcinoma,” erapeutic Advances [35] M. Scardoni, E. Vittoria, M. Volante et al., “Mixed adenoneu- in Gastroenterology,vol.10, no.5,pp.407–415, 2017. roendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the [21] F. Eren, C¸. C ¸ elikel, and B. Gull ¨ uo ¨ gl ˘ u, “Neuroendocrine differ- two components,” Neuroendocrinology, vol.100,no.4,pp. 310– entiation in gastric adenocarcinomas; correlation with tumor 316, 2015. stage and expression of VEGF and p53,” Pathology & Oncology Research,vol. 10, no.1, pp. 47–51,2004. [36] D. Furlan, R. Cerutti, A. Genasetti et al., “Microallelotyping defines the monoclonal or the polyclonal origin of mixed and [22] T.Zhang, D.Su, Z.Mao,X. Guo,L. Wang,and L.Bai, “Prognos- tic role of neuroendocrine cell differentiation in human gastric collision endocrine-exocrine tumors of the gut,” Laboratory Investigation, vol.83, no. 7,pp. 963–971, 2003. carcinoma,” International Journal of Clinical and Experimental Medicine,vol.8, pp.7837–7842,2015. [37] H. Fukui, M. Takada,T.Chiba et al., “Concurrent occurrence [23] C.Peng,L.Wang,W.Zeng,X.Yang,andY.Li,“Evaluationofthe of gastric adenocarcinoma and duodenal neuroendocrine cell staging systems for gastric cancer,” Journal of Surgical Oncology, carcinoma: a composite tumour or collision tumours?” Gut,vol. vol.108, no. 2,pp.93–105,2013. 48,no.6,pp.853–856, 2001. [24] M.Sasako, M.Saka, T.Fukagawa, H.Katai,and T.Sano,“Surgi- [38] A.N.Bartley, A.Rashid,K. F.Fournier, and S. C.Abraham, cal treatment of advanced gastric cancer: Japanese perspective,” “Neuroendocrine and mucinous dieff rentiation in signet ring Digestive Surgery, vol.24,no. 2,pp.101–107,2007. cell carcinoma of the stomach: evidence for a common cell of [25] N. S. Kapoor, J. Shamonki, M. Sim, C. T. Chung, and A. E. origin in composite tumors,” Human Pathology,vol. 42, no. 10, Giuliano, “Impact of multifocality and lymph node metastasis pp. 1420–1429, 2011. 12 Journal of Oncology [39] K. Bakkelund, R. Fossmark, I. Nordrum, and H. Waldum, “Signet Ring cells in gastric carcinomas are derived from neu- roendocrine cells,” Journal of Histochemistry & Cytochemistry, vol.54,no.6,pp.615–621, 2006. [40] T. Terada and H. Maruo, “Simultaneous large cell neuroen- docrine carcinoma and adenocarcinoma of the stomach,” World Journal of Gastroenterology,vol.17,no. 43, pp.4831–4834, 2011. [41] S.Kim, B. Park, H.S.Kim,and J. H.Kim, “Synchronous quintuple primary gastrointestinal tract malignancies: case report,” World Journal of Gastroenterology,vol. 23,no.1, pp. 173– 177, 2017. [42] Y. Nakayama, A. Higure, K. Shibao, N. Sato, N. Matayoshi, and K. Yamaguchi, “Synchronous occurrence of early neu- roendocrine carcinoma and tubular adenocarcinoma in the stomach,” Clinical Journal of Gastroenterology, vol.5,no.4,pp. 307–311, 2012. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Hindawi Publishing Corporation Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 http://www www.hindawi.com .hindawi.com V Volume 2018 olume 2013 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 International Journal of Journal of Immunology Research Endocrinology Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Submit your manuscripts at www.hindawi.com BioMed PPAR Research Research International Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2013 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018
Journal of Oncology – Hindawi Publishing Corporation
Published: Mar 12, 2019
You can share this free article with as many people as you like with the url below! We hope you enjoy this feature!
Read and print from thousands of top scholarly journals.
Already have an account? Log in
Bookmark this article. You can see your Bookmarks on your DeepDyve Library.
To save an article, log in first, or sign up for a DeepDyve account if you don’t already have one.
Copy and paste the desired citation format or use the link below to download a file formatted for EndNote
Access the full text.
Sign up today, get DeepDyve free for 14 days.
All DeepDyve websites use cookies to improve your online experience. They were placed on your computer when you launched this website. You can change your cookie settings through your browser.