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Xu L, He Z, Fu C, Wu Y, Wu A, Tian G, Huang J, Liu X, Wang Q. Case report: Coexistence of rectal signet ring cell carcinoma with neuroendocrine components. BMC Geriatr 2025; 25:382. [PMID: 40437380 PMCID: PMC12117679 DOI: 10.1186/s12877-025-06037-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/12/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND Signet ring cell carcinoma is a rare histological type among the various forms of colorectal cancers. Even rare is when it coexisted with neuroendocrine components in one tumor. To date, there is little literature reported case of colorectal cancer diagnosed as signet ring cell carcinoma with neuroendocrine components. CASE PRESENTATION This report presents a unique case manifested as obstructed defecation for more than one month but with negative endoscopic biopsies. Laparoscopic abdominoperineal resection was performed. Based on the postoperative pathology, the patient was finally diagnosed as signet ring cell carcinoma with neuroendocrine differentiation among poorly differentiated adenocarcinoma. DISCUSSION AND CONCLUSIONS We highlight the rare coexistence of signet ring cell carcinoma and neuroendocrine differentiation in this case. We also emphasize the special characteristic of intramural growth without penetrating the mucosa in signet ring cell carcinoma, further to pose the pitfalls and share lessons during our diagnosis and treatment process.
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Affiliation(s)
- Ling Xu
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Zhefeng He
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Chao Fu
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Yiyang Wu
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Anwei Wu
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Guojiang Tian
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Jianfei Huang
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Xibo Liu
- Department of Pathology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Qi Wang
- Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China.
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Li X, Lan Q, Lai W, Wu H, Xu H, Fang K, Chu Z, Zeng Y. Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p. BMC Cancer 2022; 22:928. [PMID: 36030223 PMCID: PMC9419355 DOI: 10.1186/s12885-022-09926-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/21/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction Neuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear. Materials and methods The clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT–PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored. Results NED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression. Conclusion lnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09926-1.
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Affiliation(s)
- Xiaojun Li
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qiusheng Lan
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wei Lai
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Heng Wu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Heyang Xu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kai Fang
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhonghua Chu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Yujie Zeng
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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Gallo C, Rossi RE, Cavalcoli F, Barbaro F, Boškoski I, Invernizzi P, Massironi S. Rectal neuroendocrine tumors: Current advances in management, treatment, and surveillance. World J Gastroenterol 2022; 28:1123-1138. [PMID: 35431507 PMCID: PMC8985485 DOI: 10.3748/wjg.v28.i11.1123] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/24/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Rectal neuroendocrine neoplasms (r-NENs) are considered among the most frequent digestive NENs, together with small bowel NENs. Their incidence has increased over the past few years, and this is probably due to the widespread use of endoscopic screening for colorectal cancer and the advanced endoscopic procedures available nowadays. According to the current European Neuroendocrine Tumor Society (ENETS) guidelines, well-differentiated r-NENs smaller than 10 mm should be endoscopically removed in view of their low risk of local and distant invasion. R-NENs larger than 20 mm are candidates for surgical resection because of their high risk of distant spreading and the involvement of the muscularis propria. There is an area of uncertainty regarding tumors between 10 and 20 mm, in which the metastatic risk is intermediate and the endoscopic treatment can be challenging. Once removed, the indications for surveillance are scarce and poorly codified by international guidelines, therefore in this paper, a possible algorithm is proposed.
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Affiliation(s)
- Camilla Gallo
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
| | - Roberta Elisa Rossi
- Division of HPB Surgery, Hepatology and Liver Transplantation, Department of Pathophysiology and Transplantation, University of Milan, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Federica Cavalcoli
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy
| | - Federico Barbaro
- Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore di Roma, Center for Endoscopic Research Therapeutics and Training, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome 00168, Italy
| | - Ivo Boškoski
- Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore di Roma, Center for Endoscopic Research Therapeutics and Training, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome 00168, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
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Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker? Cancers (Basel) 2021; 13:cancers13205111. [PMID: 34680258 PMCID: PMC8533893 DOI: 10.3390/cancers13205111] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/05/2021] [Accepted: 10/08/2021] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Colorectal MANECs are highly aggressive carcinomas defined by a distinct neuroendocrine morphology and positivity for synaptophysin in the neuroendocrine component. It is unclear whether a neuroendocrine differentiation in conventional adenocarcinomas without a suggestive morphology is of clinical relevance. We tested 1002 conventional colorectal carcinomas with a non-neuroendocrine morphology for synaptophysin expression and correlated the results with clinicopathological characteristics as well as patient survival and compared the survival characteristics of synaptophysin expression groups to those of true MANECs. We found no survival differences between synaptophysin expression groups within conventional colorectal adenocarcinomas. MANECs, on the other hand, showed significantly worse survival characteristics. Our data suggest that synaptophysin expression in conventional colorectal adenocarcinomas is of minor prognostic relevance and that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs. Abstract Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear. Methods: We investigated synaptophysin expression in 1002 conventional colorectal adenocarcinomas and correlated the results with clinicopathological characteristics and patient survival and compared the survival characteristics of synaptophysin expression groups to MANECs. Results: Synaptophysin expression in conventional colorectal adenocarcinomas was associated with a shortened disease-free survival (p = 0.037), but not with overall survival or disease-specific survival (DSS) in univariate analyses and without any survival impact in multivariate analyses. Patients with “true” MANECs, on the other hand, showed a significantly shorter survival than all conventional adenocarcinomas with or without synaptophysin expression in uni- and multivariate analyses (e.g., multivariate DSS: p < 0.001, HR: 5.20). Conclusions: Our study demonstrates that synaptophysin expression in conventional colorectal adenocarcinomas, in contrast to MANECs, is not associated with a significantly poorer clinical outcome when compared to adenocarcinomas without synaptophysin expression. Furthermore, our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, also strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation.
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Prognostic relevance of neuroendocrine differentiation in colorectal cancer: a population-based, propensity score matching study. Int J Colorectal Dis 2020; 35:2185-2195. [PMID: 32720185 DOI: 10.1007/s00384-020-03708-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/23/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Neuroendocrine differentiation (NED) may serve as a prognostic factor in colorectal cancer; however, the prognostic relevance of NED remains controversial. The aim of the present study was to determine whether NED influenced the survival of patients in colorectal cancer while exploring its potential interactions with other clinicopathological features. METHODS Patients with primary stage I to IV colorectal adenocarcinoma ranging between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier technique, Cox proportional hazards model, propensity score matching, and stratification analyses were employed in this study. RESULTS A total of 94,291 patients (including 101 patients with NED and 94,190 patients without NED) were included. In the univariable analyses, NED was found to be correlated with a significantly poorer overall survival (hazard ratio (HR) of death = 3.09, 95% CI 2.42-3.95, P < 0.001) and cancer-specific survival (HR of death = 3.77, 95% CI 2.94-4.83, P < 0.001). Moreover, NED remained independently correlated with overall survival (HR of death = 1.84, 95% CI 1.34-2.51, P < 0.001) and cancer-specific survival (HR of death = 2.01, 95% CI 1.45-2.79, P < 0.001) after adjusting in multivariable and propensity score analyses. Furthermore, further stratification analyses indicated that the influence of NED on survival was not affected by tumor location, differentiation, T stage, and distant metastasis status; however, it was found to be associated with lymph node metastasis. CONCLUSIONS NED is associated with poor survival outcomes among colorectal cancer patients, especially in those with positive lymph nodes.
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Bellizzi AM. Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can brown do for you? Hum Pathol 2020; 96:8-33. [PMID: 31857137 PMCID: PMC7177196 DOI: 10.1016/j.humpath.2019.12.002] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 12/08/2019] [Indexed: 02/07/2023]
Abstract
This review is based on a presentation given at the Hans Popper Hepatopathology Society companion meeting at the 2019 United States and Canadian Academy of Pathology Annual Meeting. It presents updates on the diagnosis and classification of neuroendocrine neoplasms, with an emphasis on the role of immunohistochemistry. Neuroendocrine neoplasms often present in liver biopsies as metastases of occult origin. Specific topics covered include 1. general features of neuroendocrine neoplasms, 2. general neuroendocrine marker immunohistochemistry, with discussion of the emerging marker INSM1, 3. non-small cell carcinoma with (occult) neuroendocrine differentiation, 4. the WHO Classification of neuroendocrine neoplasms, with discussion of the 2019 classification of gastroenteropancreatic neoplasms, 5. use of Ki-67 immunohistochemistry, 6. immunohistochemistry to assign site of origin in neuroendocrine metastasis of occult origin, 7. immunohistochemistry to distinguish well-differentiated neuroendocrine tumor G3 from poorly differentiated neuroendocrine carcinoma, 8. lesions frequently misdiagnosed as well-differentiated neuroendocrine tumor, and 9. required and recommended data elements for biopsies and resections with associated immunohistochemical stains. Next-generation immunohistochemistry, including lineage-restricted transcription factors (e.g., CDX2, islet 1, OTP, SATB2) and protein correlates of molecular genetic events (e.g., p53, Rb), is indispensable for the accurate diagnosis and classification of these neoplasms.
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Affiliation(s)
- Andrew M Bellizzi
- Department of Pathology, University of Iowa Hospitals and Clinics and Carver College of Medicine, Iowa City, IA, USA; University of Iowa Neuroendocrine Cancer Program, University of Iowa Hospitals and Clinics and Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
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Xu D, Lin X, Qiu X. The epithelioid gastrointestinal stromal tumor with pulmonary metastasis: A rare case report and literature review. Medicine (Baltimore) 2020; 99:e19346. [PMID: 32118771 PMCID: PMC7478712 DOI: 10.1097/md.0000000000019346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Available literature states that the histological subtype of the gastrointestinal stromal tumor (GIST) with pulmonary metastasis is often spindle cell type. To our knowledge, this is the first report of the GIST with pulmonary metastasis of very uncommon epithelioid subtype. PATIENT CONCERNS We report a 63-year-old male presenting with the symptom of bloodstained sputum without obvious inducement. The patient had no chest pain, low back pain, fatigue, fever or night sweats symptoms. DIAGNOSES Combined chest digital radiography and the history of the patient who presented with the colon GIST of the epithelioid subtype two years ago that the mass may be a metastasis tumor. Combined with morphological and immunohistochemical staining results, a pathological diagnosis of the GIST with pulmonary metastasis was considered. INTERVENTIONS Right lobectomy and partial upper lobectomy were performed. OUTCOMES The patient had not experienced any noticeable symptom and recurrent tumors at 6 months follow-up. LESSONS We report a rare case of the GIST with pulmonary metastasis of epithelioid subtype. This case is of great significance to the pathologist's clinical work. For pathologists, if an epithelioid tumor in the lung is found, it is necessary to check whether the gastrointestinal tract also has the tumor, which may be an epithelioid GIST with pulmonary metastasis.
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Ramage JK, Valle JW, Nieveen van Dijkum EJM, Sundin A, Pascher A, Couvelard A, Kloeppel G. Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need. Neuroendocrinology 2019; 108:45-53. [PMID: 30219817 DOI: 10.1159/000493767] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/14/2018] [Indexed: 12/15/2022]
Abstract
The subject of colorectal neuroendocrine neoplasms (NENs), subdivided into well-differentiated NENs, termed neuroendocrine tumours (NETs; grade (G) 1 and 2), and poorly differentiated NENs, termed neuroendocrine carcinomas (NECs; G3) according to the 2010 World Health Organisation (WHO) classification, has arguably not had as much attention or study as NENs occurring in other sites. Colorectal NETs and NECs are however easier to study than many others since they are usually not difficult to remove and are increasingly detected because of intensified colorectal cancer screening and surveillance programmes. Colorectal NETs and NECs show site-specific heterogeneity with variable behaviour and different therapeutic options; these various aspects provide unique challenges. Because of bowel cancer screening programmes, colorectal NENs, like conventional adenocarcinomas, may be diagnosed at a stage that is associated with improved survival. In this article we intend to describe and define areas of unmet needs relating to the epidemiology, classification, pathology, diagnosis and therapy of colorectal NETs (including NETs G3), colorectal NECs, and finally, mixed adeno-neuroendocrine carcinomas (MANECs) by reviewing and discussing the relevant literature.
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Affiliation(s)
- John K Ramage
- Department Gastroenterology, Hampshire Hospitals NHS Trust, Kings College Hospital ENETS centre of Excellence, Basingstoke, United
| | - Juan W Valle
- Department of Medical Oncology, University of Manchester, The Christie ENETS Centre of Excellence, Manchester, United Kingdom
| | | | - Anders Sundin
- Department of Radiology, Institution Surgical Sciences, Uppsala University and ENETS centre of excellence, Uppsala University Hopsital, Uppsala, Sweden
| | - Andreas Pascher
- Department of Surgery, Charité Universitaetsmedizin Berlin, Berlin, Germany
- Department of Visceral and Transplant Surgery, University of Muenster, Muenster, Germany
| | - Anne Couvelard
- Department of Pathology, Bichat Hospital AP-HP and University of Paris Diderot, Paris, France
| | - Guenter Kloeppel
- Department of Pathology, Technical University Munich, Munich, Germany
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