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Yin L, Wang R, Ma X, Jiang K, Hu Y, Zhao X, Zhang L, Wang Z, Long T, Lu M, Li J, Sun Y. Exploring the expression of DLL3 in gastroenteropancreatic neuroendocrine neoplasms and its potential diagnostic value. Sci Rep 2025; 15:3287. [PMID: 39865119 PMCID: PMC11770191 DOI: 10.1038/s41598-025-86237-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 01/09/2025] [Indexed: 01/28/2025] Open
Abstract
Delta-like protein (DLL3) is a novel therapeutic target. DLL3 expression in gastroenteropancreatic neuroendocrine tumors (GEP-NECs) is poorly understood, complicating the distinction between well-differentiated neuroendocrine tumors G3 (NET G3) and poorly differentiated NEC. DLL3 immunohistochemistry (IHC) was performed on 248 primary GEP-NECs, correlating with clinicopathological parameters, NE markers, PD-L1, Ki67 index, and prognosis. Achaete-scute complex-like 1 (ASCL1) IHC was performed on some GEP-NECs. DLL3 IHC was conducted on 36 GEP-NETs, 29 gastric adenocarcinomas (GACs), and metastatic tumors (9 lymph node metastases and 19 distant metastases). DLL3 expression rates were 54.8% in GEP-NECs at the primary site, associated with small cell neuroendocrine carcinoma (SCNEC) (p < 0.001), chemotherapy before baseline (p = 0.015), and at least two NE markers (p = 0.048). DLL3 expression in metastatic GEP-NECs was similar to that of primary tumors. Expression rates in NET G1, NET G2, NET G3, and GACs were 0%, 0%, 15.8%, and 0%, respectively, highlighting DLL3 as a powerful tool for identifying poorly differentiated NEC. DLL3 expression was related to ASCL1 in GEP-NECs, especially in SCNEC. It was not correlated with progression-free survival (PFS) or overall survival(OS), regardless of cutoff value (1%, 50%, 75%). In conclusion, DLL3 targeted therapy may offer potential for the treatment of poorly differentiated NEC of the digestive system, although further studies are needed to validate its efficacy.
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Affiliation(s)
- L Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - R Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - K Jiang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Y Hu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - L Zhang
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - Z Wang
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - T Long
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - M Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - J Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Y Sun
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Milewska-Kranc A, Ćwikła JB, Kolasinska-Ćwikła A. The Role of Receptor-Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors. Cancers (Basel) 2023; 16:116. [PMID: 38201544 PMCID: PMC10778465 DOI: 10.3390/cancers16010116] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1-SSTR5). Understanding receptor-ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor-ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.
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Affiliation(s)
| | - Jarosław B. Ćwikła
- School of Medicine, University of Warmia and Mazury, Aleja Warszawska 30, 10-082 Olsztyn, Poland
- Diagnostic Therapeutic Center–Gammed, Lelechowska 5, 02-351 Warsaw, Poland
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Stiefel R, Lehmann K, Winder T, Siebenhüner AR. What have we learnt from the past - would treatment decisions for GEP-NET patients differ between 2012 to 2016 by the new recommendations in 2022? BMC Cancer 2023; 23:148. [PMID: 36782152 PMCID: PMC9926660 DOI: 10.1186/s12885-023-10567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 01/19/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment sequences exists. The aim of this study was to analyse outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of European Society of Medical Oncology (ESMO) 2020 for GEP-NETs. METHODS Patients were included in this retrospective single-center analysis from 2012-2016. All patients suffering from a GEP-NET, who were screened, treated or evaluated at ENETS Center in Zurich, Switzerland were included in analysis. Patients with any other diagnosis of NET were not included. We used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages and treatment sequences. RESULTS Overall, we identified 256 GEP-NETs, most in advanced stage (62%) and located in small intestine tract or pancreatic gland. Survival depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed early but also in advanced stages, usually followed by Somatostatine-Agonist modalities. In distant disease (Stage IV), we investigated a positive effect of PFS after treatment with Somatostatine Analogues (SSA) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21 - 0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26 - 0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection. Kaplan Meier distributions predict shorter OS in distant disease (Stage IV), (Figure. 1; HR, 2.06; 95% CI, 1.46 - 2.89; log-rank test, p < 0.001). CONCLUSION This retrospective analysis presents a great overview of all patients', disease and treatment characteristics of GEP-NETs at ENETS Center in Zurich, Switzerland. We illustrated survival (PFS) depending on implemented therapies. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs. The results of this project may define GEP-NET patients' selection for upcoming clinical prospective studies.
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Affiliation(s)
- Rahel Stiefel
- grid.414526.00000 0004 0518 665XMedical Oncology and Hematology, Triemli Hospital Zurich, Zurich, Switzerland
| | - Kuno Lehmann
- grid.7400.30000 0004 1937 0650Department of Surgery and Transplantation, University Hospital and University of Zurich, Zurich, Switzerland
| | - Thomas Winder
- grid.413250.10000 0000 9585 4754Internal Medicine II, Hematology, Oncology and Gastroenterology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria ,grid.7400.30000 0004 1937 0650University of Zurich, Zurich, Switzerland
| | - Alexander R. Siebenhüner
- grid.7400.30000 0004 1937 0650Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland ,Clinic of Internal Medicine and Oncology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
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Grande E, Rodriguez-Antona C, López C, Alonso-Gordoa T, Benavent M, Capdevila J, Teulé A, Custodio A, Sevilla I, Hernando J, Gajate P, Molina-Cerrillo J, Díez JJ, Santos M, Lanillos J, García-Carbonero R. Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial. Oncologist 2021; 26:941-949. [PMID: 34190375 DOI: 10.1002/onco.13885] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/23/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs). METHODS Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1. RESULTS From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6-18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations. CONCLUSION SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062) IMPLICATIONS FOR PRACTICE: Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.
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Affiliation(s)
- Enrique Grande
- Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain
| | - Cristina Rodriguez-Antona
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Carlos López
- Medical Oncology, Hospital Universitario Marqués de Valdecilla, Instituto de investigación sanitaria Valdecilla (IDIVAL), Santander, Spain
| | | | - Marta Benavent
- Medical Oncology Department, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain
| | - Jaume Capdevila
- Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology, Barcelona, Spain
| | - Alex Teulé
- Institut Català d'Oncologia (ICO)-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Spain
| | - Ana Custodio
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Isabel Sevilla
- Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Málaga (IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain
| | - Jorge Hernando
- Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology, Barcelona, Spain
| | - Pablo Gajate
- Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Juan José Díez
- Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro Segovia de Arana, Madrid, Spain
| | - María Santos
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
| | - Javier Lanillos
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
| | - Rocío García-Carbonero
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre (i+12), Universidad Complutense de Madrid (UCM), Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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Burden of Carcinoid Heart Disease in Patients With Carcinoid Syndrome Initiating Somatostatin Analogues. Clin Ther 2019; 41:1716-1723.e2. [DOI: 10.1016/j.clinthera.2019.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/17/2019] [Accepted: 06/21/2019] [Indexed: 12/25/2022]
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Gu D, Hu Y, Ding H, Wei J, Chen K, Liu H, Zeng M, Tian J. CT radiomics may predict the grade of pancreatic neuroendocrine tumors: a multicenter study. Eur Radiol 2019; 29:6880-6890. [PMID: 31227882 DOI: 10.1007/s00330-019-06176-x] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 03/06/2019] [Accepted: 03/15/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To develop and validate a radiomics-based nomogram for preoperatively predicting grade 1 and grade 2/3 tumors in patients with pancreatic neuroendocrine tumors (PNETs). METHODS One hundred thirty-eight patients derived from two institutions with pathologically confirmed PNETs (104 in the training cohort and 34 in the validation cohort) were included in this retrospective study. A total of 853 radiomic features were extracted from arterial and portal venous phase CT images respectively. Minimum redundancy maximum relevance and random forest methods were adopted for the significant radiomic feature selection and radiomic signature construction. A fusion radiomic signature was generated by combining both the single-phase signatures. The nomogram based on a comprehensive model incorporating the clinical risk factors and the fusion radiomic signature was established, and decision curve analysis was applied for clinical use. RESULTS The fusion radiomic signature has significant association with histologic grade (p < 0.001). The nomogram integrating independent clinical risk factor tumor margin and fusion radiomic signature showed strong discrimination with an area under the curve (AUC) of 0.974 (95% CI 0.950-0.998) in the training cohort and 0.902 (95% CI 0.798-1.000) in the validation cohort with good calibration. Decision curve analysis verified the clinical usefulness of the predictive nomogram. CONCLUSION We proposed a comprehensive nomogram consisting of tumor margin and fusion radiomic signature as a powerful tool to predict grade 1 and grade 2/3 PNET preoperatively and assist the clinical decision-making for PNET patients. KEY POINTS • Radiomic signature has strong discriminatory ability for the histologic grade of PNETs. • Arterial and portal venous phase CT imaging are complementary for the prediction of PNET grading. • The comprehensive nomogram outperformed clinical factors in assisting therapy strategy in PNET patients.
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Affiliation(s)
- Dongsheng Gu
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No. 95 East Zhongguancun Road, Beijing, 100190, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yabin Hu
- Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, 180 Fenglin Rd., Shanghai, 200032, China.,Department of Radiology, Affiliated Hospital (Laoshan hospital) of Qingdao University, Qingdao, 266061, Shandong, China
| | - Hui Ding
- Department of Radiology, Affiliated Hospital (Laoshan hospital) of Qingdao University, Qingdao, 266061, Shandong, China
| | - Jingwei Wei
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No. 95 East Zhongguancun Road, Beijing, 100190, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ke Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hao Liu
- Department of Radiology, Central Hospital of ZiBo, Shandong, 255036, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, 180 Fenglin Rd., Shanghai, 200032, China.
| | - Jie Tian
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No. 95 East Zhongguancun Road, Beijing, 100190, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, 100191, China. .,Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shanxi, 710126, China.
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Joish VN, Shah S, Tierce JC, Patel D, McKee C, Lapuerta P, Zacks J. Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis. Future Oncol 2019; 15:1397-1406. [PMID: 30734573 DOI: 10.2217/fon-2018-0960] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2 = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.
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Affiliation(s)
- Vijay N Joish
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA
| | | | | | | | - Chad McKee
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA
| | - Pablo Lapuerta
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA
| | - Jerome Zacks
- Icahn School of Medicine, Center for Carcinoid and Neuroendocrine Tumors, Mount Sinai Health System, New York, NY 10029, USA
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Abstract
Immunohistochemistry (IHC) can be applied to diagnostic aspects of pathologic examination to provide aid in assignment of lineage and histologic type of cancer. Increasingly, however, IHC is widely used to provide prognostic and predictive (theranostic) information about the neoplastic disease. A refinement of theranostic application of IHC can be seen in the use of "genomic probing" where antibody staining results are directly correlated with an underlying genetic alteration in the tumor (somatic mutations) and/or the patient (germline constitution). All these aspects of IHC find their best use in guiding the oncologists in the optimal use of therapy for the patients.
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Affiliation(s)
| | | | - Semir Vranić
- College of Medicine, Qatar University, Doha, Qatar
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Henfling M, Perren A, Schmitt AM, Saddig CM, Starke AA, Riedl RG, Versleijen-Jonkers YMH, Sprij-Mooij DM, Ramaekers FCS, Hofland L, Speel EJM. The IGF pathway is activated in insulinomas but downregulated in metastatic disease. Endocr Relat Cancer 2018; 25:ERC-18-0222. [PMID: 30021864 DOI: 10.1530/erc-18-0222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 02/03/2023]
Abstract
Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.
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Affiliation(s)
- Mieke Henfling
- M Henfling, Genetics & Cell Biology, Maastricht University - Location Randwyck, Maastricht, Netherlands
| | - Aurel Perren
- A Perren, University of Bern, Institute of Pathology, Bern, Switzerland
| | - Anja Maria Schmitt
- A Schmitt, Department of Pathology, University of Bern, Bern, Switzerland
| | - Christiane M Saddig
- C Saddig, Insulinoma and GEP-Tumor Center Neuss-Düsseldorf, Klinik für Endokrine Chirurgie, Stadtische Kliniken Neuss Lukaskrankenhaus GmbH, Neuss, Germany
| | - Achim A Starke
- A Starke, Insulinoma and GEP-Tumor Center Neuss-Düsseldorf, Klinik für Endokrine Chirurgie, Stadtische Kliniken Neuss Lukaskrankenhaus GmbH, Neuss, Germany
| | - Robert G Riedl
- R Riedl, Pathology, Zuyderland Medisch Centrum Heerlen, Heerlen, Netherlands
| | | | - Diane M Sprij-Mooij
- D Sprij-Mooij, Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Netherlands
| | - Frans C S Ramaekers
- F Ramaekers, Molecular Cell Biology, Maastricht University, Maastricht, Netherlands
| | - Leo Hofland
- L Hofland, Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Netherlands
| | - Ernst-Jan M Speel
- E Speel, Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
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Dizdar L, Oesterwind KA, Riemer JC, Werner TA, Mersch S, Möhlendick B, Schütte SC, Verde PE, Raba K, Topp SA, Stoecklein NH, Esposito I, Knoefel WT, Krieg A. Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia. Oncotarget 2018; 8:8369-8382. [PMID: 28039474 PMCID: PMC5352407 DOI: 10.18632/oncotarget.14207] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 11/22/2016] [Indexed: 02/07/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.
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Affiliation(s)
- Levent Dizdar
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Kira A Oesterwind
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Jasmin C Riemer
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Thomas A Werner
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Sabrina Mersch
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Birte Möhlendick
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Sina C Schütte
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Pablo E Verde
- Coordination Centre for Clinical Trials, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Katharina Raba
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Stefan A Topp
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Nikolas H Stoecklein
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Wolfram T Knoefel
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Andreas Krieg
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
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11
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Viúdez A, Carvalho FLF, Maleki Z, Zahurak M, Laheru D, Stark A, Azad NS, Wolfgang CL, Baylin S, Herman JG, De Jesus-Acosta A. A new immunohistochemistry prognostic score (IPS) for recurrence and survival in resected pancreatic neuroendocrine tumors (PanNET). Oncotarget 2018; 7:24950-61. [PMID: 26894863 PMCID: PMC5041882 DOI: 10.18632/oncotarget.7436] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 01/23/2016] [Indexed: 01/04/2023] Open
Abstract
Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS). Our IPS could be a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET.
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Affiliation(s)
- Antonio Viúdez
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.,Department of Medical Oncology, Complejo Hospitalario de Navarra-Instituto de Investigaciones Sanitarias de Navarra-IDISNA, Pamplona, Navarra, Spain
| | - Filipe L F Carvalho
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Zahra Maleki
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Marianna Zahurak
- The Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Daniel Laheru
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Alejandro Stark
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Nilofer S Azad
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Christopher L Wolfgang
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Stephen Baylin
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - James G Herman
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Ana De Jesus-Acosta
- Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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12
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Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A, Faggiano A. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer 2018; 25:R11-R29. [PMID: 29066503 DOI: 10.1530/erc-17-0269] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.
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Affiliation(s)
- Vincenzo Marotta
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Maria Rosaria Ambrosio
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Marta Bondanelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy
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13
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Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors. Pancreas 2017; 46:151-156. [PMID: 27759712 PMCID: PMC5595066 DOI: 10.1097/mpa.0000000000000734] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.
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14
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Liu DJ, Fu XL, Liu W, Zheng LY, Zhang JF, Huo YM, Li J, Hua R, Liu Q, Sun YW. Clinicopathological, treatment, and prognosis study of 43 gastric neuroendocrine carcinomas. World J Gastroenterol 2017; 23:516-524. [PMID: 28210088 PMCID: PMC5291857 DOI: 10.3748/wjg.v23.i3.516] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 12/05/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas (G-NECs) which occur rarely but are highly malignant and clinically challenging.
METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria.
RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half (48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases (72.09%), and liver metastasis was found in 6 cases (13.95%). Follow-up information was got for 40 patients. Twenty-three die of this disease with a median survival of 31 mo (range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR (30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence.
CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Large Cell/drug therapy
- Carcinoma, Large Cell/mortality
- Carcinoma, Large Cell/pathology
- Carcinoma, Large Cell/surgery
- Carcinoma, Neuroendocrine/drug therapy
- Carcinoma, Neuroendocrine/mortality
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/surgery
- Carcinoma, Small Cell/drug therapy
- Carcinoma, Small Cell/mortality
- Carcinoma, Small Cell/pathology
- Carcinoma, Small Cell/surgery
- Chemotherapy, Adjuvant/methods
- Female
- Follow-Up Studies
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/secondary
- Liver Neoplasms/surgery
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/therapy
- Prognosis
- Retrospective Studies
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/mortality
- Stomach Neoplasms/pathology
- Stomach Neoplasms/surgery
- Survival Analysis
- Survival Rate
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15
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Oberg K, Krenning E, Sundin A, Bodei L, Kidd M, Tesselaar M, Ambrosini V, Baum RP, Kulke M, Pavel M, Cwikla J, Drozdov I, Falconi M, Fazio N, Frilling A, Jensen R, Koopmans K, Korse T, Kwekkeboom D, Maecke H, Paganelli G, Salazar R, Severi S, Strosberg J, Prasad V, Scarpa A, Grossman A, Walenkamp A, Cives M, Virgolini I, Kjaer A, Modlin IM. A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocr Connect 2016; 5:174-187. [PMID: 27582247 PMCID: PMC5045519 DOI: 10.1530/ec-16-0043] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 08/31/2016] [Indexed: 12/17/2022]
Abstract
The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.
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Affiliation(s)
| | | | | | - Lisa Bodei
- Memorial Sloan Kettering Cancer CenterNew York, New York, USA
| | - Mark Kidd
- Wren LaboratoriesBranford, Connecticut, USA
| | | | | | | | - Matthew Kulke
- Dana Farber Cancer InstituteBoston, Massachusetts, USA
| | | | | | | | | | - Nicola Fazio
- IEO (European Institute of Oncology)Milan, Italy
| | | | - Robert Jensen
- National Institutes of HealthBethesda, Maryland, USA
| | | | - Tiny Korse
- Netherlands Cancer InstituteAmsterdam, Netherlands
| | | | | | - Giovanni Paganelli
- Instituto Scientifico Romagnolo per lo Studio e la Cura dei TumoriMeldola, Italy
| | | | - Stefano Severi
- Instituto Scientifico Romagnolo per lo Studio e la Cura dei TumoriMeldola, Italy
| | | | | | | | | | | | - Mauro Cives
- H. Lee Moffitt Cancer CenterTampa, Florida, USA
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16
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Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.
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17
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Besa C, Ward S, Cui Y, Jajamovich G, Kim M, Taouli B. Neuroendocrine liver metastases: Value of apparent diffusion coefficient and enhancement ratios for characterization of histopathologic grade. J Magn Reson Imaging 2016; 44:1432-1441. [PMID: 27227756 DOI: 10.1002/jmri.25320] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 05/07/2016] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To assess the value of apparent diffusion coefficient (ADC) measured with diffusion-weighted imaging (DWI) and enhancement ratios (ER) measured with contrast-enhanced T1-weighted imaging (CE-T1WI) for the characterization of histopathologic tumor grade of neuroendocrine tumor liver metastases (NETLM). MATERIALS AND METHODS Twenty-two patients with pathology-proven NETLM and pretreatment 1.5 Tesla (T) and 3T MRI including DWI were included in this Institutional Review Board-approved retrospective study. ADC histogram parameters, including mean, minimum (min), skewness, and kurtosis as well as ER, were computed for all lesions. Tumor grading was based on the World Health Organization 2010 classification. Kruskal-Wallis and Mann-Whitney test were used to assess for differences in ADC and ER between different tumor grades. MRI parameters were correlated with pathologic findings using Spearman correlation test. Receiver operating characteristic analysis was performed to determine optimum thresholds for predicting tumor grade. RESULTS Forty-eight NETLM (mean size 3.5 cm) were analyzed with the following grade distribution: G1 (n = 25), G2 (n = 16), and G3 (n = 7). ADC-mean (×10-3 mm2 /s) of G3 tumors (0.87 ± 0.43) was significantly lower than that of G1 (1.47 ± 0.63) and G2 (1.27 ± 0.63; P = 0.042). A weak significant negative correlation was observed between ADC and tumor grade (ADC-mean: r = -0.33, P = 0.02; ADC-min: r = -0.37, P = 0.01) and Ki-67 (ADC-mean: r = -0.31, P = 0.03; ADC-min: r = -0.39, P = 0.007). AUROC, sensitivity and specificity of ADC-mean/ADC-min/ER (measured at the early arterial phase) for differentiation of G3 versus G1-G2 were 0.80/0.76/0.67, 100%/50%/70%, and 68.4%/84.2%/66.6%, respectively. CONCLUSION ADC is a promising marker for characterization of histopathologic grade of NETLM. These results should be confirmed in a prospective study. J. Magn. Reson. Imaging 2016;44:1432-1441.
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Affiliation(s)
- Cecilia Besa
- Department of Radiology, Body MRI, Icahn School of Medicine at Mount Sinai, New York, USA.,Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Stephen Ward
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Yong Cui
- Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA.,Department of Radiology, Peking University Cancer Hospital & Beijing Cancer Hospital, Beijing, China
| | - Guido Jajamovich
- Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Michelle Kim
- Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Bachir Taouli
- Department of Radiology, Body MRI, Icahn School of Medicine at Mount Sinai, New York, USA.,Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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18
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Bongiovanni A, Riva N, Ricci M, Liverani C, La Manna F, De Vita A, Foca F, Mercatali L, Severi S, Amadori D, Ibrahim T. First-line chemotherapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma. Onco Targets Ther 2015; 8:3613-9. [PMID: 26664145 PMCID: PMC4671803 DOI: 10.2147/ott.s91971] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background and aim To investigate the efficacy of platinum-based chemotherapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma (mGEP-NEC) and define predictive and prognostic factors. Methods Twenty mGEP-NEC patients were treated with cisplatin or carboplatin/etoposide between April 2010 and October 2014. Both large-cell and small-cell histologies were included. Cisplatin 25 mg/m2 was administered on days 1–3 followed by etoposide 100 mg/m2 on days 1–3 every 21 days. Carboplatin 300 mg/m2 was administered on day 1 followed by etoposide 100 mg/m2 on days 1–3. Results Of the 19 evaluable patients, 13 obtained a partial response, four showed stable disease, and two progressed. Median overall survival (mOS) was 13.5 months and median progression-free survival (mPFS) was 10.9 months. Gallium-68 positron emission tomography/computerizsed tomography-positive patients had a higher, albeit not significantly, OS than those with negative results (75% vs 34.3% at 18 months; P=0.06). mPFS was 19.3 and 6.3 months (P<0.01) in mGEP-NEC patients with Ki67 ≤55% or >55%, respectively. mOS was 8.1 months in the latter group but was not reached in the Ki67 ≤55% group (P-value =0.039). Patients with a lower body mass index (BMI) had a better prognosis in terms of both OS and PFS. Patients with BMI ≥25 had a mOS of 11.7 months (P=0.0293) and a mPFS of 6.2 months (P=0.0057). Conclusion Platinum-based chemotherapy showed good efficacy in mGEP-NEC patients. Those with Ki67 ≤55%, positive Gallium-68 positron emission tomography/computerized tomography and BMI <25 had a better prognosis.
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Affiliation(s)
- Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Nada Riva
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Marianna Ricci
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Chiara Liverani
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Federico La Manna
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Alessandro De Vita
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Laura Mercatali
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Stefano Severi
- Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
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19
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Oberg K, Modlin IM, De Herder W, Pavel M, Klimstra D, Frilling A, Metz DC, Heaney A, Kwekkeboom D, Strosberg J, Meyer T, Moss SF, Washington K, Wolin E, Liu E, Goldenring J. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol 2015; 16:e435-e446. [PMID: 26370353 PMCID: PMC5023063 DOI: 10.1016/s1470-2045(15)00186-2] [Citation(s) in RCA: 212] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 02/06/2023]
Abstract
Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.
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Affiliation(s)
- Kjell Oberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | | | - Wouter De Herder
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, Netherlands
| | | | - David Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David C Metz
- Division of Gastroenterology, University of Pennsylvania Health System, Philadelphia, PA, USA
| | - Anthony Heaney
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Dik Kwekkeboom
- Department of Nuclear Medicine, Erasmus Medical Centre, Rotterdam, Netherlands
| | | | - Timothy Meyer
- University College London Cancer Institute, London, UK
| | - Steven F Moss
- Brown University, Liver Research Center, Providence, RI, USA
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Edward Wolin
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Eric Liu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James Goldenring
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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Du S, Ni J, Weng L, Ma F, Li S, Wang W, Sang X, Lu X, Zhong S, Mao Y. Aggressive Locoregional Treatment Improves the Outcome of Liver Metastases from Grade 3 Gastroenteropancreatic Neuroendocrine Tumors. Medicine (Baltimore) 2015; 94:e1429. [PMID: 26313798 PMCID: PMC4602914 DOI: 10.1097/md.0000000000001429] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare, and there is no report specifically dealing with patients of liver metastases from G3 GEP NETs.From January 2004 to January 2014, 36 conservative patients with G3 GEP NET liver metastases were retrospectively identified from 3 hepatobiliary centers in China. The clinical features and treatment outcomes were analyzed.Aggressive locoregional treatments (LT, including cytoreductive surgery, radiofrequency ablation, and liver-directed intra-arterial intervention) and systemic therapy (ST) were introduced separately or combined, with 26 (72%) patients receiving resection of primary tumor and/or hepatic metastases, 12 patients receiving non-surgical locoregional interventions (NSLRIs), and 22 patients receiving certain kind of STs. Median overall survival (OS) was 20.0 months (95% confidence interval [CI]: 8.9-31.1 months) and survival rates were 62.6%, 30.1%, and 19.8%, at 1, 3, and 5 years, respectively. The median OS was 9.0 months (95%CI: 3.3-14.7 months) for patients receiving only STs (n = 6), 19 months (95%CI: 1.3-36.8 months) for patients receiving LT followed by STs (n = 16), and 101 months (95%CI: 0.0-210.2 months) for patients receiving only LT (n = 12). Moreover, compared with those receiving only ST or best supportive care, patients given certain types of LTs had higher rates of symptom alleviation (3/8 versus 20/23). On univariate analysis, positive prognostic factors of survival were pancreatic primary tumor (P = 0.013), normal total bilirubin level (P = 0.035), receiving surgery (P = 0.034), receiving NSLRI (P = 0.014), and sum of diameters of remnant tumor < 5 cm (P = 0.008). On multivariate analyses, pancreatic primary tumor (P = 0.015), normal total bilirubin level (P = 0.002), and sum of diameters of remnant tumor < 5 cm (P = 0.001) remained to be independent prognostic factors.For patients with G3 GEP NET liver metastases, aggressive LTs may improve clinical outcomes. Larger studies with prospective design are warranted to consolidate these results, and to discover the most appropriate seletion criteria for patients to undergo different kinds of aggressive LTs and to find the most effective combinations, with or without ST.
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Affiliation(s)
- Shunda Du
- From the Department of Liver Surgery (SD, JN, LW, XS, XL, SZ, YM); Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and PUMC, Beijing (FM); Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou (SL); and Department of Pathology, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China (WW)
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Sun L, Qian Q, Sun G, Mackey LV, Fuselier JA, Coy DH, Yu CY. Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II. J Drug Target 2015. [PMID: 26211366 DOI: 10.3109/1061186x.2015.1066794] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization. MATERIALS AND METHODS The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells. CONCLUSION The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.
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Affiliation(s)
- Lichun Sun
- a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China .,b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and
| | - Qingqing Qian
- a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China
| | - Guangchun Sun
- a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China
| | - L Vienna Mackey
- b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and
| | - Joseph A Fuselier
- b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and
| | - David H Coy
- b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and
| | - Cui-Yun Yu
- b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.,c Department of Pharmacy , Institute of Pharmacy & Pharmacology, University of South China , Hengyang , China
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Komminoth P, Perren A. Was ist neu in der Pathologie neuroendokriner Tumoren des Pankreas? DER PATHOLOGE 2015; 36:220-8. [DOI: 10.1007/s00292-015-0023-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Intravoxel incoherent motion diffusion-weighted imaging of pancreatic neuroendocrine tumors: prediction of the histologic grade using pure diffusion coefficient and tumor size. Invest Radiol 2015; 49:396-402. [PMID: 24500090 DOI: 10.1097/rli.0000000000000028] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE The purpose of this study was to assess the value of intravoxel incoherent motion and diffusion-weighted imaging for predicting the histologic grade of pancreatic neuroendocrine tumors (PNETs). MATERIALS AND METHODS Forty patients with surgically diagnosed PNETs who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging with a series of 10 b values (0-1000 s/mm(2), were included in this institutional review board-approved retrospective study. The apparent diffusion coefficient (ADC(total)), the intravoxel incoherent motion parameters (pure diffusion coefficient [D], pseudodiffusion coefficient [D(*)], and perfusion fraction [f]) were measured on the tumors. Histologic grading was performed on the basis of the World Health Organization 2010 classification system. Logistic regression analysis and receiver operating curve analysis were performed to identify the significant factors predicting the histologic grades. RESULTS Grades 2 and 3 tumors were significantly larger than grade 1 tumors (average 3.62 cm vs 2.17 cm in diameter; P=0.001). Grades 2 and 3 tumors showed significantly lower D values than did grade 1 tumors (0.95 vs 1.21×10(-3) mm(2)/s; P=0.009), although the ADC(total) showed no significant difference. When any of the following 2 criteria was used, (a) tumor size smaller than 2.0 cm in diameter and (b) D value greater than 1.2×10(-3) mm(2)/s, the sensitivity, specificity, and positive predictive value for diagnosing grade 1 PNETs were 76.92%, 100%, and 100%, respectively. CONCLUSIONS Pure diffusion coefficient (D) is possibly a better marker than ADC(total) is for differentiating grade 1 from grade 2 or 3 PNET and, combined with tumor size, can predict grade 1 PNET with a high specificity.
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Kleiman DA, Beninato T, Sultan S, Crowley MJP, Finnerty B, Kumar R, Panarelli NC, Liu YF, Lieberman MD, Seandel M, Evans T, Elemento O, Zarnegar R, Fahey TJ. Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors. Ann Surg Oncol 2014; 21 Suppl 4:S672-9. [PMID: 24854489 DOI: 10.1245/s10434-014-3787-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined. METHODS Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index. RESULTS Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p < 0.001). Hypermethylation of the UCHL1 promoter was commonly observed among metastatic primary tumors and metastases (those with the lowest UCHL1 expression) but not among localized tumors (p < 0.001). Poor staining (<50 %) for UCHL1 was observed in 27 % of localized tumors compared with 87 % of metastatic tumors (p = 0.001). The presence of <50 % staining for UCHL1 was 88 % sensitive and 73 % specific for identifying metastatic disease. In contrast, there was no association between Ki-67 index and metastatic disease. In multivariable analysis, only UCHL1 staining <50 % [odds ratio (OR) 24.5, p = 0.035] and vascular invasion (OR 38.4, p = 0.03) were independent risk factors for metastatic disease at the time of initial surgery. CONCLUSIONS Loss of UCHL1 expression by CpG promoter hypermethylation is associated with metastatic GEP-NETs. Extent of UCHL1 staining should be explored as a potentially clinically useful adjunct to Ki-67 index in evaluating GEP-NETs for aggressive features.
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Affiliation(s)
- David A Kleiman
- Division of Endocrine and Minimally Invasive Surgery, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA
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25
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Carlinfante G, Baccarini P, Berretti D, Cassetti T, Cavina M, Conigliaro R, De Pellegrin A, Di Tommaso L, Fabbri C, Fornelli A, Frasoldati A, Gardini G, Losi L, Maccio L, Manta R, Pagano N, Sassatelli R, Serra S, Camellini L. Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases. Virchows Arch 2014; 465:49-55. [PMID: 24807732 DOI: 10.1007/s00428-014-1585-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 04/09/2014] [Accepted: 04/24/2014] [Indexed: 12/30/2022]
Abstract
The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted κ statistic 0.77; 95 % confidence interval (95 % CI) 0.60-0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3-99.3) and G3 tumors (100.0 %; 95 % CI 92.8-100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4-88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8-100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted κ 0.82; 95 % CI 0.64-1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P-NETs, and it may be useful for their preoperative classification.
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Affiliation(s)
- Gabriele Carlinfante
- Department of Pathology, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, 42123, Reggio Emilia, Italy,
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26
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Krieg A, Mersch S, Boeck I, Dizdar L, Weihe E, Hilal Z, Krausch M, Möhlendick B, Topp SA, Piekorz RP, Huckenbeck W, Stoecklein NH, Anlauf M, Knoefel WT. New model for gastroenteropancreatic large-cell neuroendocrine carcinoma: establishment of two clinically relevant cell lines. PLoS One 2014; 9:e88713. [PMID: 24551139 PMCID: PMC3925161 DOI: 10.1371/journal.pone.0088713] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 01/09/2014] [Indexed: 12/12/2022] Open
Abstract
Recently, a novel WHO-classification has been introduced that divided gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) according to their proliferation index into G1- or G2-neuroendocrine tumors (NET) and poorly differentiated small-cell or large-cell G3-neuroendocrine carcinomas (NEC). Our knowledge on primary NECs of the GEP-system is limited due to the rarity of these tumors and chemotherapeutic concepts of highly aggressive NEC do not provide convincing results. The aim of this study was to establish a reliable cell line model for NEC that could be helpful in identifying novel druggable molecular targets. Cell lines were established from liver (NEC-DUE1) or lymph node metastases (NEC-DUE2) from large cell NECs of the gastroesophageal junction and the large intestine, respectively. Morphological characteristics and expression of neuroendocrine markers were extensively analyzed. Chromosomal aberrations were mapped by array comparative genomic hybridization and DNA profiling was analyzed by DNA fingerprinting. In vitro and in vivo tumorigenicity was evaluated and the sensitivity against chemotherapeutic agents assessed. Both cell lines exhibited typical morphological and molecular features of large cell NEC. In vitro and in vivo experiments demonstrated that both cell lines retained their malignant properties. Whereas NEC-DUE1 and -DUE2 were resistant to chemotherapeutic drugs such as cisplatin, etoposide and oxaliplatin, a high sensitivity to 5-fluorouracil was observed for the NEC-DUE1 cell line. Taken together, we established and characterized the first GEP large-cell NEC cell lines that might serve as a helpful tool not only to understand the biology of these tumors, but also to establish novel targeted therapies in a preclinical setup.
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Affiliation(s)
- Andreas Krieg
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
- * E-mail:
| | - Sabrina Mersch
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Inga Boeck
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Levent Dizdar
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Eberhard Weihe
- Institute of Anatomy and Cell Biology, Department of Molecular Neuroscience, Philipps University Marburg, Marburg, Germany
| | - Zena Hilal
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Markus Krausch
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Birte Möhlendick
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Stefan A. Topp
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Roland P. Piekorz
- Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany
| | - Wolfgang Huckenbeck
- Institute of Forensic Medicine, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Nikolas H. Stoecklein
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Martin Anlauf
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Wolfram T. Knoefel
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
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Zerbi A, Capitanio V, Boninsegna L, Delle Fave G, Pasquali C, Rindi G, Campana D, Falconi M, the members of the AISP-Network Study Group. Treatment of malignant pancreatic neuroendocrine neoplasms: middle-term (2-year) outcomes of a prospective observational multicentre study. HPB (Oxford) 2013; 15:935-43. [PMID: 23472667 PMCID: PMC3843611 DOI: 10.1111/hpb.12065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 01/11/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Information on malignant pancreatic neuroendocrine neoplasms (pNENs) is mostly from retrospective studies in highly selected patients. The aim of this prospective, multicentre study was to assess treatment and outcomes of malignant pNENs in clinical practice. PATIENTS AND METHODS Consecutive patients with newly diagnosed, histologically-proven pNENs were included and followed-up for 2 years. Tumours were defined as malignant when nodal or distant metastases were present or invasion of extrapancreatic structures/organs was evident. RESULTS A total of 140 patients with malignant pNENs were included. Ninety-eight patients (70.0%) underwent a surgical resection (76 radical and 22 palliative). Other non-surgical treatments were used in 101 patients (72.1%): somatostatin analogues (n = 63), chemotherapy (n = 30), ablative treatments (n = 15) and peptide-receptor radionuclide therapy (n = 14). No relationship was observed between the 2010 WHO classification and type of treatment. A surgical resection was more often performed in incidentally detected tumours located in the pancreas body tail. Two-year progression-free survival was 63.8%: 82% after a radical resection, 44% after a palliative resection and 41% without a resection. A radical resection and Ki67 proliferative index >5% and >10% were the only significant prognostic determinants in multivariate analysis. CONCLUSIONS A radical resection is the cornerstone treatment of malignant pNENs and represents, together with Ki67 assessment, the most powerful prognostic factor for 2-year outcomes.
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Affiliation(s)
- Alessandro Zerbi
- Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research CenterMilan, Italy
| | - Vanessa Capitanio
- Pancreas Unit, Department of Surgery, San Raffaele Scientific InstituteMilan, Italy
| | - Letizia Boninsegna
- Department of Surgery, University of Verona, Policlinico ‘GB Rossi’Verona, Italy
| | | | | | - Guido Rindi
- Institute of Pathology, Università Cattolica–Policlinico GemelliRome, Italy
| | - Davide Campana
- Department of Medicine, University of Bologna, Sant'Orsola Malpighi HospitalBologna, Italy
| | - Massimo Falconi
- Department of Surgery, University of Verona, Policlinico ‘GB Rossi’Verona, Italy
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Abstract
Objective. Balloon enteroscopy (BE) and capsule enteroscopy (CE) are enteroscopy methods that allow examination and treatment of the small bowel. Before the CE and BE era, the small intestine was difficult to access for investigation. Small intestinal tumours are infrequent conditions, but about half of them are malignant. Materials and Methods. A total of 303 BEs were performed in 179 patients. Oral insertion was performed in 240 and anal in 63 BEs. Indications for the procedure in our patients with small bowel tumours were anaemia and/or bleeding, obstruction, suspicion of carcinoid tumour, or suspicion of Peutz-Jeghers syndrome. Results. In 50 of our 179 patients (28%), we diagnosed some small intestinal tumours: hamartomas in Peutz-Jeghers syndrome in 16 patients, adenocarcinoma in 7, lymphoma in 6, carcinoid tumour in 4, melanoma and stromal tumour in 3, adenoma, lipoma, and inflammatory polyps in 2, and granular cell tumour, cavernous lymphangioma, fibrolipoma, Cronkhite-Canada polyps, and metastatic involvement in individual cases. Conclusion. BE facilitates exploration and treatment of the small intestine. The procedure is generally safe and useful. BE and CE are essential modalities for the management of small intestinal diseases.
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Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging. AJR Am J Roentgenol 2013; 201:811-24. [PMID: 24059370 DOI: 10.2214/ajr.12.10240] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The purposes of this article are to review the current management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) based on the 2012 National Comprehensive Cancer Network guidelines and to describe the role of imaging in a multidisciplinary approach. CONCLUSION The management of GEP-NETs has become complex, requiring a multidisciplinary approach. The World Health Organization classification of GEP-NETs has been revised; the U.S. Food and Drug Administration has approved molecular targeted agents (sunitinib, everolimus) for the treatment of pancreatic NETs; and the National Comprehensive Cancer Network clinical practice guidelines have been updated.
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Abstract
PURPOSE OF REVIEW To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.
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Affiliation(s)
- Tetsuhide Ito
- aDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan bDigestive Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
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Schieren G, Bölke E, Scherer A, Raffel A, Gerber PA, Kröpil P, Schott M, Hamilton J, Hayman A, Knoefel WT, Budach W, Matuschek C. Severe everolimus-induced steatohepatis: a case report. Eur J Med Res 2013; 18:22. [PMID: 23822543 PMCID: PMC3706391 DOI: 10.1186/2047-783x-18-22] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 06/11/2013] [Indexed: 12/22/2022] Open
Abstract
The mammalian target of rapamycin inhibitors are normally favored as immunosuppressant agents for solid organ transplantation such as kidney, liver or heart. Only in recent years have they been increasingly administered for the treatment of neuroendocrine tumors. Even though mammalian target of rapamycin inhibitors are known to exhibit specific side effects, everolimus-related severe hepatic steatosis has not as yet been described in the literature. We report the case of a 76-year-old man who developed severe hepatic steatosis within four weeks of treatment with everolimus as concomitant tumor therapy for a progressively growing neuroendocrine carcinoma of the ileum. A diagnosis of hepatic steatosis was established using computer tomography and fibroscan©. Other underlying causes for steatosis hepatis could be excluded. Further studies are warranted to explain the underlying mechanisms.
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Affiliation(s)
- Gisela Schieren
- Department of Radiation Oncology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
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Galván JA, Astudillo A, Vallina A, Fonseca PJ, Gómez-Izquierdo L, García-Carbonero R, González MV. Epithelial-mesenchymal transition markers in the differential diagnosis of gastroenteropancreatic neuroendocrine tumors. Am J Clin Pathol 2013; 140:61-72. [PMID: 23765535 DOI: 10.1309/ajcpiv40istbxrax] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVES To elucidate the role of epithelial-mesenchymal transition markers in gastroenteropancreatic neuroendocrine tumors (GEP NETs) and the potential usefulness in their clinical management. METHODS One hundred ten GEP NET paraffin-embedded samples were immunohistochemically analyzed for E-cadherin, N-cadherin, β-catenin, vimentin, Snail1, Snail2, Twist, and Foxc2 protein expression. RESULTS The 5-year survival rate was reduced for those patients showing high Snail1 protein levels, a cytoplasmic E-cadherin pattern, reduced N-cadherin expression, and loss of E-cadherin/β-catenin adhesion complex integrity at the cell membrane. Interestingly, high β-catenin expression was useful in identifying a grade 1 NET subgroup with a favorable clinical course. Importantly, it also helped to discriminate small-cell vs large-cell grade 3 neuroendocrine carcinomas. CONCLUSIONS β-Catenin and N-cadherin immunohistochemical detection might be a useful tool in the differential diagnosis of small-cell vs large-cell G3 neuroendocrine carcinomas. High Snail1 and Foxc2 expression is associated with the invasion and metastatic spread of GEP NETs.
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Affiliation(s)
- Jose A. Galván
- Laboratorio del Banco de Tumores, Instituto Universitario de Oncología del Principado de Asturias, Obra Social CajAstur, Oviedo, Spain
| | - Aurora Astudillo
- Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Aitana Vallina
- Laboratorio del Banco de Tumores, Instituto Universitario de Oncología del Principado de Asturias, Obra Social CajAstur, Oviedo, Spain
| | - Paula J. Fonseca
- Servicio de Oncología Médica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Lourdes Gómez-Izquierdo
- Servicio de Anatomía Patológica, Hospital Universitario Virgen del Rocío–Instituto de Biomedicina de Sevilla, Sevilla, Spain
| | - Rocío García-Carbonero
- Servicio de Oncología Médica, Hospital Universitario Virgen del Rocío–Instituto de Biomedicina de Sevilla, Sevilla, Spain
| | - Maria Victoria González
- Unidad de Oncología de Cabeza y Cuello, Instituto Universitario de Oncología del Principado de Asturias, Obra Social CajAstur, Oviedo, Spain
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Fazio N, Spada F, Giovannini M. Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. Cancer Treat Rev 2013; 39:270-274. [PMID: 22819619 DOI: 10.1016/j.ctrv.2012.06.009] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 06/25/2012] [Indexed: 12/12/2022]
Abstract
Neuroendocrine tumors (NET) are classified according to the Ki67 in low-intermediate grade (Ki67<20%) and high grade (Ki67>20%). The NET of the latter group are also known as neuroendocrine carcinoma (NEC), and their prognosis is dismail. While in the former group biotherapy and radionuclide therapy can be proposed, chemotherapy represents the only treatment usually proposed for NEC. Cisplatin/etoposide combination is usually chosen based on the rationale that NEC are clinically similar to small cell lung cancer. However, evidence for cisplatin/etoposide in NEC is poor and controversial, and different schedules and response rate have been published so far. These aspects, combined with the heterogeneous characteristics of NEC, prompt us to have some doubt in considering cisplatin/etoposide as the gold standard. Some evidence exists that carboplatin can be used instead of cisplatin and irinotecan instead of etoposide without reducing efficacy. Furthermore other drugs, as gemcitabine, oxaliplatin or temozolomide can be evaluated in NEC with non-neuroendocrine component or in mixed adenoneuroendocrine carcinomas. NEC are a category of NET that should be deeply studied to verify if the response to cisplatin/etoposide is homogeneous related to the different Ki67, different morphology and/or different primary site.
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Affiliation(s)
- Nicola Fazio
- Unit of Upper Gastrointestinal and Neuroendocrine Tumors, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2013; 20:74-9. [PMID: 23247096 DOI: 10.1097/med.0b013e32835cb529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs. Best Pract Res Clin Gastroenterol 2012; 26:705-717. [PMID: 23582914 DOI: 10.1016/j.bpg.2013.01.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 01/10/2013] [Indexed: 01/31/2023]
Abstract
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a heterogeneous group of neoplasms. In the last few decades, due to a substantial rise in incidence and prevalence, GEP-NETs have been included among the most common tumours of the gastrointestinal tract. Diagnosis could be challenging and a significant number of patients present with metastatic or unresectable disease. The development of appropriate tools for standardised prognostic stratification and the introduction of effective target therapies have opened new horizons for planning tailored surgical or medical management and follow-up programs for these complex neoplasms. An overview on the GEP-NETs' diagnostic and prognostic criteria proposed by the recently published WHO classification and ENETS and UICC TNM staging systems is presented, focussing on their impact on the clinical and therapeutical approaches.
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Affiliation(s)
- Paola Capelli
- Department of Pathology and Diagnostics & ARC-NET Research Centre, University of Verona, Verona, Italy.
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Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. JOURNAL OF ONCOLOGY 2012; 2012:705036. [PMID: 23209466 PMCID: PMC3503399 DOI: 10.1155/2012/705036] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/16/2012] [Indexed: 12/12/2022]
Abstract
Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. Heterozygous MEN 1 germline mutations have been detected in about 70–80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of the RET protooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specific RET mutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.
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Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol 2012; 47:941-960. [PMID: 22886480 PMCID: PMC3754804 DOI: 10.1007/s00535-012-0642-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 06/23/2012] [Indexed: 02/08/2023]
Abstract
Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years.
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Affiliation(s)
- Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Building 10, Room 9C-103, Bethesda, MD 20892, USA
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