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Bartsch DK, Krasser‐Gercke N, Jesinghaus M, Görlach J, Eilsberger F, Rinke A, Maurer E. Results of Surgical Reintervention After Suboptimal Initial Resection for Locoregional Neuroendocrine Tumors of the Small Intestine. World J Surg 2025; 49:1343-1350. [PMID: 40238178 PMCID: PMC12058433 DOI: 10.1002/wjs.12582] [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: 01/19/2025] [Revised: 03/09/2025] [Accepted: 03/23/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Complete resection is the only chance for cure in small intestine neuroendocrine neoplasms (SI-NEN). Previous ENETS guidelines proposed standards for the surgery of SI-NEN, which should be followed to provide long-term disease-free survival. AIM To analyze the results of reintervention for locoregional SI-NEN (stages I-III) after suboptimal initial resection. METHODS Perioperative characteristics of all patients who underwent surgical reintervention after suboptimal initial resection (SIR) of locoregional SI-NEN were retrieved from a prospective database. Patient characteristics, initial and redo procedures, imaging before reintervention, pathological results of SIR, and after reintervention, including missed primary tumors and lymph node metastases, were retrospectively analyzed. RESULTS During a 15 years period, 21 of 93 (22%) patients had surgical reinterventions after SIR. In 20 of 21 (95%) cases, the initial resection was performed outside an ENETS center of excellence. Ten (48%) of those cases were emergency operations because of the bowel obstruction or bowel bleeding. Seven SIR (33%) cases were performed laparoscopically, and in another 5 (24%) cases, a complete endoscopic mucosa resection was performed. Imaging before reintervention visualized residual disease in 15 of 21 (71%) patients. Surgical reintervention included either lymphadenectomy alone (LAD, n = 3) or small bowel resection plus systematic LAD (n = 12) or right hemicolectomy/ileocecal resection with systematic LAD (n = 6), respectively. In 19 of 21 (90%) patients, a R0 resection could be achieved. One patient (5%) experienced postoperative clinically relevant complications. According to pathology, in 10 (48%) patients lymph node metastases, in 6 (29%) patients additional primary tumors, and in 5 (24%) patients, both lymph nodes metastases and primary tumors were left behind in the SIR. After mean follow-up of 52 months, 16 (76%) of 21 patients were free of disease, 4 (19%) patients were alive with disease, and 1 patient deceased of an unrelated cause. CONCLUSION The proposed standards to resect locoregional SI-NEN should be followed to avoid SIR, although the prognosis after adequate surgical reintervention is good.
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Affiliation(s)
- Detlef K. Bartsch
- Department of Visceral‐, Thoracic‐ and Vascular SurgeryPhilipps‐University MarburgMarburgGermany
| | - Norman Krasser‐Gercke
- Department of Visceral‐, Thoracic‐ and Vascular SurgeryPhilipps‐University MarburgMarburgGermany
| | | | - Jannis Görlach
- Department of Diagnostic and Interventional RadiologyPhilipps‐University MarburgMarburgGermany
| | | | - Anja Rinke
- Department of Gastroenterology and EndocrinologyPhilipps‐University MarburgMarburgGermany
| | - Elisabeth Maurer
- Department of Visceral‐, Thoracic‐ and Vascular SurgeryPhilipps‐University MarburgMarburgGermany
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Danieli M, Bertani E. ASO Author Reflections: Primary Tumor Resection in Metastatic Small Intestinal Neuroendocrine Tumors: A Step Toward Standardized Management? Ann Surg Oncol 2025; 32:2185-2186. [PMID: 39722085 DOI: 10.1245/s10434-024-16718-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 12/28/2024]
Affiliation(s)
- Maria Danieli
- University of Milan, Milan, Italy
- Division of Digestive Surgery IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Emilio Bertani
- Division of Digestive Surgery IEO, European Institute of Oncology IRCCS, Milan, Italy.
- Neuroendocrine Surgery Tumor Unit, IEO, European Institute of Oncology IRCCS, Milan, Italy.
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Kianmanesh R, Amroun KL, Rhaiem R, Jazi AHD, Moazenzadeh H, Rached L, Zimmermann P, Durame A, Renard Y, Ravenet A, Bouche O, Deguelte S. C-reactive protein and digestive pathologies: A narrative review for daily clinical use. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2025; 30:10. [PMID: 40200962 PMCID: PMC11974606 DOI: 10.4103/jrms.jrms_537_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 11/02/2024] [Accepted: 01/20/2025] [Indexed: 04/10/2025]
Abstract
The aim of this narrative review is to familiarize clinicians, especially digestive surgeons, to adequately use of serum C-reactive protein as a reliable noninvasive biomarker in diverse practical clinical situations. We hope that the review will help clinicians for their decision-making when facing various digestive diseases including operative and nonoperative pathologies such as anastomotic leakage, pancreatitis, emergency situation, and digestive cancer management and prognosis.
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Affiliation(s)
- Reza Kianmanesh
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Koceila Lamine Amroun
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
- Department of Clinical Research, Aging and Fragility Unit UR 3797, Hospital University, Reims, France
| | - Rami Rhaiem
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Amir Hossein Davarpanah Jazi
- Department of Minimally Invasive and Bariatric Surgery, Hazrate Fatemeh Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hashem Moazenzadeh
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Linda Rached
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Perrine Zimmermann
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Adrien Durame
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Yohann Renard
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Ambroise Ravenet
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
| | - Olivier Bouche
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of Digestive Oncology, CHU Robert Debré, Reims, France
| | - Sophie Deguelte
- Reims Medical Faculty, Champagne Ardenne University, Ardenne, France
- Department of General, Digestive and Endocrine Surgery, Christian Cabrol Hospital University, Reims, France
- Department of Clinical Research, Aging and Fragility Unit UR 3797, Hospital University, Reims, France
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Pavlidis ET, Galanis IN, Pavlidis TE. Critical considerations for the management of gastrointestinal mixed neuroendocrine non-neuroendocrine neoplasms and pure neuroendocrine carcinomas. World J Gastrointest Oncol 2024; 16:4559-4564. [PMID: 39678788 PMCID: PMC11577359 DOI: 10.4251/wjgo.v16.i12.4559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/25/2024] [Accepted: 10/18/2024] [Indexed: 11/12/2024] Open
Abstract
Mixed neuroendocrine non-neuroendocrine neoplasms constitute rare tumors that are located mainly in the gastrointestinal (GI) tract and have high degrees of malignancy, and the frequency of these tumors has been increasing. They consist of a neuroendocrine neoplastic component with another component of adenocarcinoma usually and have a dismal prognosis. The rare GI pure neuroendocrine carcinoma is highly aggressive and requires complex and extensive management since a genetic distinction exists between it and GI non-neuroendocrine neoplasms, which are generally slow-growing lesions. The most common GI-mixed neuroendocrine non-neuroendocrine neoplasms are colorectal, followed by gastric, mainly in the gastroesophageal junction. Current imaging modalities of nuclear medicine and radiology play important roles in the accuracy of diagnosis. Liquid biopsy may contribute to early detection and timely diagnosis. Ultrasonography, either endoscopic or abdominal, is a technique that contributes to a diagnosis; additionally, contrast-enhanced ultrasonography is very helpful in follow-up appointments. Histopathology establishes a definite diagnosis and stage by evaluating the cell differentiation grade and the cell proliferation index Ki67. The genetic profile can be valuable in diagnosis and gene therapy. Surgical resection with wide lymphadenectomy, whenever possible, and adjuvant chemotherapy constitute the main therapeutic management strategies. Targeted therapy and immunotherapy achieve encouraging results.
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Affiliation(s)
- Efstathios T Pavlidis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis N Galanis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros E Pavlidis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Lamarca A, Bartsch DK, Caplin M, Kos-Kudla B, Kjaer A, Partelli S, Rinke A, Janson ET, Thirlwell C, van Velthuysen MLF, Vullierme MP, Pavel M. European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours. J Neuroendocrinol 2024; 36:e13423. [PMID: 38977327 DOI: 10.1111/jne.13423] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/28/2024] [Accepted: 06/02/2024] [Indexed: 07/10/2024]
Abstract
Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.
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Affiliation(s)
- Angela Lamarca
- Department of Oncology - Onco Health Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Detlef K Bartsch
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumors, ENETS Center of Excellence, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University of Copenhagen-Rigshospitalet, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano Partelli
- Pancreas Translational and Clinical Research Centre, Pancreatic and Transplant Surgery Unit, Vita-Salute San Raffaele University, Milan, Italy
| | - Anja Rinke
- Department of Gastroenterology, University Hospital Marburg and Philipps University Marburg, Marburg, Germany
| | - Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology Unit, Uppsala University, Uppsala, Sweden
| | - Christina Thirlwell
- Department of Medical Oncology, University of Exeter Medical School, Exeter, UK
| | | | - Marie-Pierre Vullierme
- Department of Radiology, Paul Brousse University Hospital, AP-HP-University Paris Saclay, Villejuif, France
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, ENETS Center of Excellence Erlangen, CCC Erlangen- EMN, and Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
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Holzer K, Bartsch DK. [Gastroenteropancreatic neuroendocrine neoplasms-Surgery in a multimodal concept]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:773-782. [PMID: 38935138 DOI: 10.1007/s00104-024-02117-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 06/28/2024]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are mainly found in the small intestine and pancreas. The course of the disease in patients is highly variable and depends on the degree of differentiation (G1-G3) of the neoplasm. The potential for metastasis formation of GEP-NEN is high even with good differentiation (G1). Lymph node metastases and, in many cases, liver metastases are also often found. Less common are bone metastases or peritoneal carcinomas. The treatment of these GEP-NENs is surgical, whenever possible. If an R0 resection with removal of all lymph node and liver metastases is successful, the prognosis of the patients is excellent. Patients with diffuse liver or bone metastases can no longer be cured by surgery alone. The long-term survival of these patients is nowadays possible due to the availability of drugs (e.g., somatostatin analogues, tyrosine kinase inhibitors), peptide receptor radionuclide therapy (PRRT) and liver-directed procedures, with a good quality of life.
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Affiliation(s)
- K Holzer
- Klinik für Viszeral‑, Thorax- und Gefäßchirurgie, Universitätsklinikum Marburg, Baldingerstraße, Marburg, Deutschland.
| | - D K Bartsch
- Klinik für Viszeral‑, Thorax- und Gefäßchirurgie, Universitätsklinikum Marburg, Baldingerstraße, Marburg, Deutschland
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Vulasala SS, Virarkar M, Gopireddy D, Waters R, Alkhasawneh A, Awad Z, Maxwell J, Ramani N, Kumar S, Onteddu N, Morani AC. Small Bowel Neuroendocrine Neoplasms-A Review. J Comput Assist Tomogr 2024; 48:563-576. [PMID: 38110305 DOI: 10.1097/rct.0000000000001541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
Neuroendocrine neoplasms (NENs) are rapidly evolving small bowel tumors, and the patients are asymptomatic at the initial stages. Metastases are commonly observed at the time of presentation and diagnosis. This review addresses the small bowel NEN (SB-NEN) and its molecular, histological, and imaging features, which aid diagnosis and therapy guidance. Somatic cell number alterations and epigenetic mutations are studied to be responsible for sporadic and familial SB-NEN. The review also describes the grading of SB-NEN in addition to rare histological findings such as mixed neuroendocrine-non-NENs. Anatomic and nuclear imaging with conventional computed tomography, magnetic resonance imaging, computed tomographic enterography, and positron emission tomography are adopted in clinical practice for diagnosing, staging, and follow-up of NEN. Along with the characteristic imaging features of SB-NEN, the therapeutic aspects of imaging, such as peptide receptor radionuclide therapy, are discussed in this review.
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Affiliation(s)
- Sai Swarupa Vulasala
- From the Department of Radiology, University of Florida College of Medicine, Jacksonville
| | - Mayur Virarkar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL
| | - Dheeraj Gopireddy
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL
| | - Rebecca Waters
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Ziad Awad
- Surgery, University of Florida College of Medicine, Jacksonville, FL
| | - Jessica Maxwell
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center
| | - Nisha Ramani
- Department of Pathology, Michael E. DeBakey VA Medical Center, Houston, TX
| | - Sindhu Kumar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL
| | - Nirmal Onteddu
- Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL
| | - Ajaykumar C Morani
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX
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Cui LJ, Yu FH, Cheng ZX, Su F, Chen YY, Tan HY. Prognostic value of inflammation-related biomarkers in patients with gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis. J Neuroendocrinol 2024; 36:e13381. [PMID: 38468159 DOI: 10.1111/jne.13381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 01/29/2024] [Accepted: 02/22/2024] [Indexed: 03/13/2024]
Abstract
Hematological indicators of chronic systemic inflammation are significant biomarkers for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We performed a systematic review and meta-analysis to assess the impact of certain factors on the overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) of patients with GEP-NENs. These factors include the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and C-reactive protein (CRP) levels. After searching the Medline, Embase, and Cochrane Library databases from January 1, 2000 to October 20, 2022 and the American Society of Clinical Oncology conference proceedings from January 1, 2017, hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted. Subgroup analyses were conducted to identify the origins of heterogeneity and examine the impact of factor grouping. The effects of the cut-off values and sample size were assessed by meta-regression. The results revealed that higher NLRs, PLRs, and CRP levels were associated with shorter OS (HR = 2.09, 95% CI = 1.55-2.8; HR = 1.79, 95% CI = 1.40-2.28; and HR = 2.88, 95% CI = 2.09-3.95, respectively; all p < 0.001). Higher NLRs and lower LMRs were associated with shorter DFS (HR = 3.34, 95% CI = 2.11-5.29 and HR = 2.71, 95% CI = 2.27-3.24, respectively; both p < 0.001). Higher PLRs and CRP levels were correlated with shorter PFS (HR = 3.48, 95% CI = 1.34-9.03, p = 0.01 and HR = 3.14, 95% CI = 1.63-6.08, p = 0.001). As demonstrated in the research, hematological indicators of systemic inflammation are promising biomarkers for GEP-NEN assessment.
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Affiliation(s)
- Ling-Jun Cui
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Fu-Huan Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Zi-Xuan Cheng
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Fei Su
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Ying-Ying Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
| | - Huang-Ying Tan
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
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Eneholm J, Beka E, Kotán R, Gimm O. A retrospective study comparing minimally invasive versus open surgical resection of small intestinal neuroendocrine neoplasms at a tertiary referral center. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:107936. [PMID: 38176259 DOI: 10.1016/j.ejso.2023.107936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 12/07/2023] [Accepted: 12/22/2023] [Indexed: 01/06/2024]
Abstract
INTRODUCTION Neuroendocrine neoplasms (SI-NEN) are the commonest malignancies of the small intestine. Traditionally, surgical treatment for SI-NEN has been open surgery. PURPOSE The purpose of this study was to compare minimally invasive surgery (MIS) with the traditional open surgery approach for treating SI-NEN in a Swedish population. METHODS Patients with histopathological confirmed SI-NEN who underwent open surgery or MIS resection within 2009-2021 were extracted from the hospital's medical records. RESULTS 65 patients were included in this study, with 35 (54 %) undergoing MIS and 30 (46 %) undergoing open surgery. We found no statistically significant difference (p = 0.173) in the frequency of R0 resections (MIS group n = 34 (97 %), open surgery group n = 26 (87 %)). Nor was there a significant difference (p = 0.101) when comparing the median number of resected lymph nodes (MIS group n = 13.5, open surgery group n = 10). A post-operative paralytic ileus was more often reported (p = 0.052) in the MIS group (n = 9, 26 %) compared to the open surgery group (n = 2, 7 %). In light of this, the days of hospital stay did not differ significantly (MIS group median = 6, IQR (5-8), open surgery group median = 6, IQR (5-9)). The Kaplan-Meier analysis did not reveal differences concerning cancer-related deaths (p = 0.109). CONCLUSION The results from this study support that a MIS approach for the treatment of SI-NEN may not be inferior to open surgery. The higher number of resected lymph nodes and R0 resections may even speak in favor for a MIS approach. More studies with a longer time of observation are needed to further support this conclusion.
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Affiliation(s)
- Johan Eneholm
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, 58185, Linköping, Sweden
| | - Ervin Beka
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, 58185, Linköping, Sweden
| | - Róbert Kotán
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, 58185, Linköping, Sweden
| | - Oliver Gimm
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, 58185, Linköping, Sweden.
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Graf SD, Keber CU, Hattesohl A, Teply-Szymanski J, Hattesohl S, Guder M, Gercke N, Di Fazio P, Slater EP, Jesinghaus M, Denkert C, Bartsch DK, Lehman B. Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells. J Neuroendocrinol 2024; 36:e13364. [PMID: 38246597 DOI: 10.1111/jne.13364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/09/2023] [Accepted: 12/08/2023] [Indexed: 01/23/2024]
Abstract
Neuroendocrine tumors of the small intestine (SI-NETs) often develop lymph node metastasis (LNM)-induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI-NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF-). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF- within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF- formalin-fixed, paraffin-embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549-gene expression panel were differentially expressed in MF+ patients compared to MF-. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2-fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF-, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF- patients. RT-qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF- patients. IHC staining confirmed the enrichment of α-smooth muscle actin-positive fibrosis in MF+ compared to MF- patients with corresponding increase of COMP-expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer-associated fibroblasts enriched environment, it seems to be a promising new target for MF research.
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Affiliation(s)
- Sebastian D Graf
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Corinna U Keber
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Akira Hattesohl
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Julia Teply-Szymanski
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Sophia Hattesohl
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Marc Guder
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Norman Gercke
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Emily P Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Moritz Jesinghaus
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Carsten Denkert
- Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Bettina Lehman
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
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11
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Chetcuti Zammit S, Sidhu R. Small bowel neuroendocrine tumours - casting the net wide. Curr Opin Gastroenterol 2023; 39:200-210. [PMID: 37144538 DOI: 10.1097/mog.0000000000000917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
PURPOSE OF REVIEW Our aim is to provide an overview of small bowel neuroendocrine tumours (NETs), clinical presentation, diagnosis algorithm and management options. We also highlight the latest evidence on management and suggest areas for future research. RECENT FINDINGS Dodecanetetraacetic acid (DOTATATE) scan can detect NETs with an improved sensitivity than when compared with an Octreotide scan. It is complimentary to small bowel endoscopy that provides mucosal views and allows the delineation of small lesions undetectable on imaging. Surgical resection is the best management modality even in metastatic disease. Prognosis can be improved with the administration of somatostatin analogues and Evarolimus as second-line therapies. SUMMARY NETs are heterogenous tumours affecting most commonly the distal small bowel as single or multiple lesions. Their secretary behaviour can lead to symptoms, most commonly diarrhoea and weight loss. Metastases to the liver are associated with carcinoid syndrome.
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Affiliation(s)
| | - Reena Sidhu
- Academic Department of Gastroenterology, Royal Hallamshire Hospital, Department of Infection, Immunity and Cardiovascular Diseases, University of Sheffield, Sheffield, UK
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Pavlidis ET, Pavlidis TE. Molecular factors, diagnosis and management of gastrointestinal tract neuroendocrine tumors: An update. World J Clin Cases 2022; 10:9573-9587. [PMID: 36186187 PMCID: PMC9516923 DOI: 10.12998/wjcc.v10.i27.9573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/16/2022] [Accepted: 08/17/2022] [Indexed: 02/05/2023] Open
Abstract
The prevalence of gastrointestinal neuroendocrine tumors (GI-NETs) is increasing, and despite recent advances in their therapy, it remains inadequate in patients with advanced well-differentiated neuroendocrine tumors. These tumors present many challenges concerning the molecular basis and genomic profile, pathophysiology, clinicopathological features, histopathologic classification, diagnosis and treatment. There has been an ongoing debate on diagnostic criteria and clinical behavior, and various changes have been made over the last few years. Neuroendocrine carcinoma of the gastrointestinal system is a rare but highly malignant neoplasm that is genetically distinct from gastrointestinal system neuroendocrine tumors (NETs). The diagnosis and management have changed over the past decade. Emerging novel biomarkers and metabolic players in cancer cells are useful and promising new diagnostic tools. Progress in positron emission tomography-computerized tomography and scintigraphy with new radioactive agents (64Cu-DOTATATE or 68Ga-DOTATATE) replacing enough octreoscan, has improved further the current diagnostic imaging. Promising results provide targeted therapies with biological agents, new drugs, chemotherapy and immunotherapy. However, the role of surgery is important, since it is the cornerstone of management. Simultaneous resection of small bowel NETs with synchronous liver metastases is a surgical challenge. Endoscopy offers novel options not only for diagnosis but also for interventional management. The therapeutic option should be individualized based on current multidisciplinary information.
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Affiliation(s)
- Efstathios Theodoros Pavlidis
- Department of 2nd Surgical Propedeutic, Hippocration Hospital, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Theodoros Efstathios Pavlidis
- Department of 2nd Surgical Propedeutic, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Jesinghaus M, Poppinga J, Lehman B, Maurer E, Ramaswamy A, Grass A, Di Fazio P, Rinke A, Denkert C, Bartsch DK. Frequency and Prognostic Significance of Intertumoural Heterogeneity in Multifocal Jejunoileal Neuroendocrine Tumours. Cancers (Basel) 2022; 14:3963. [PMID: 36010956 PMCID: PMC9406343 DOI: 10.3390/cancers14163963] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival. METHODS We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival. RESULTS Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival (p = n.s.). DISCUSSION Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required.
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Affiliation(s)
- Moritz Jesinghaus
- Institute of Pathology, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Jelte Poppinga
- Department of Visceral, Thoracic and Vascular Surgery, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Bettina Lehman
- Department of Visceral, Thoracic and Vascular Surgery, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Elisabeth Maurer
- Department of Visceral, Thoracic and Vascular Surgery, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Annette Ramaswamy
- Institute of Pathology, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Albert Grass
- Institute of Pathology, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Anja Rinke
- Department of Gastroenterology, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Carsten Denkert
- Institute of Pathology, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
| | - Detlef K. Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Phillips University Marburg and University Hospital Marburg, 35043 Marburg, Germany
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Bartsch DK, Windel S, Kanngießer V, Jesinghaus M, Holzer K, Rinke A, Maurer E. Vessel-Sparing Lymphadenectomy Should Be Performed in Small Intestine Neuroendocrine Neoplasms. Cancers (Basel) 2022; 14:cancers14153610. [PMID: 35892869 PMCID: PMC9332577 DOI: 10.3390/cancers14153610] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/15/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Primary tumor resection with lymphadenectomy in small intestine neuroendocrine neoplasms potentially requires extensive small bowel resections due to central lymph node metastases and mesenteric fibrosis. Retrograde vessel-sparing lymphadenectomy (VS-LA) might be a sufficient method for avoiding local recurrence and for sparing the small bowel at the same time. We retrospectively analyzed clinical, surgical and pathological data of 50 patients with SI-NENs who exclusively underwent small bowel resections; half of them received conventional lymphadenectomy and 25 underwent VS-LA. VS-LA resulted in shorter resected bowel segments (median 40 cm vs. 65 cm, p = 0.007) with similar rates of local R0 resections (72% vs. 84%) and number of resected lymph nodes (median 13 vs. 13). Postoperative complications occurred significantly less in the vessel-sparing group. VS-LA should be the preferred surgical method in small bowel resections for SI-NENs. Abstract Introduction: The goal of primary tumor resection with lymphadenectomy (PTR) in small intestine neuroendocrine neoplasms (SI-NENs) is to avoid local recurrence while sparing as much of the small bowel as possible, even in the case of extensive mesenteric fibrosis. The results of PTR with retrograde vessel-sparing lymphadenectomy (VS-LA) were compared to those of conventional lymphadenectomy (Con-LA). Methods: Prospectively collected clinical, surgical and pathological data of consecutive patients with SI-NENs who underwent small bowel resections were retrospectively analyzed regarding the resection technique performed. Results: In a 7-year period, 50 of 102 patients with SI-NENs had only small bowel resections; of those, 25 were VS-LA and 25 were Con-LA. Patients with VS-LA had tendentially more advanced diseases with slightly higher rates of abdominal pain, mesenteric shrinkage and more level III lymph node involvement compared to patients with Con-LA. VS-LA, however, resulted in shorter resected bowel segments (median 40 cm vs. 65 cm, p = 0.007) with similar rates of local R0 resections (72% vs. 84%) and resected lymph nodes (median 13 vs. 13). Postoperative clinically relevant complications occurred in 1 of 25 (4%) in the VS-LA and in 7 of 25 (28%) patients in the Con-LA group (p = 0.02). Three months after surgery, 1 of 25 (4%) patients of the VS-LA group and 10 of 25 (40%) patients in the Con-LA group (p = 0.002) complained about abdominal pain. One of eight patients in the VS-LA group and two of thirteen patients in the Con-LA group who had completely resected stage III disease complained about diarrhea (p = 0.31). Conclusion: VS-LA seems to be oncologically safe and should be considered in small bowel resections for SI-NENs.
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Affiliation(s)
- Detlef K. Bartsch
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany; (D.K.B.); (S.W.); (V.K.); (K.H.)
| | - Sebastian Windel
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany; (D.K.B.); (S.W.); (V.K.); (K.H.)
| | - Veit Kanngießer
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany; (D.K.B.); (S.W.); (V.K.); (K.H.)
| | - Moritz Jesinghaus
- Institute of Pathology, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany;
| | - Katharina Holzer
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany; (D.K.B.); (S.W.); (V.K.); (K.H.)
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany;
| | - Elisabeth Maurer
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany; (D.K.B.); (S.W.); (V.K.); (K.H.)
- Correspondence:
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