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Angerilli V, Sabella G, Simbolo M, Lagano V, Centonze G, Gentili M, Mangogna A, Coppa J, Munari G, Businello G, Borga C, Schiavi F, Pusceddu S, Leporati R, Oldani S, Fassan M, Milione M. Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms. Br J Cancer 2024; 131:159-170. [PMID: 38729995 PMCID: PMC11231306 DOI: 10.1038/s41416-024-02705-8] [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: 11/14/2023] [Revised: 04/20/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND High-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55). METHODS We analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1. RESULTS Frequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival. CONCLUSIONS This study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.
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Affiliation(s)
| | - Giovanna Sabella
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Lagano
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marco Gentili
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute of Pathological Anatomy, Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giada Munari
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Chiara Borga
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Sara Pusceddu
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Rita Leporati
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Simone Oldani
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
| | - Massimo Milione
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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Modica R, Liccardi A, Minotta R, Cannavale G, Benevento E, Colao A. Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms. Expert Rev Endocrinol Metab 2024; 19:49-61. [PMID: 37936421 DOI: 10.1080/17446651.2023.2279540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
INTRODUCTION Despite the fact that important advances in research on neuroendocrine neoplasms (NENs) have been made, consistent data about their pathogenetic mechanism are still lacking. Furthermore, different primary sites may recognize different pathogenetic mechanisms. AREAS COVERED This review analyzes the possible biological and molecular mechanisms that may lead to NEN onset and progression in different organs. Through extensive research of the literature, risk factors including hypercholesterolemia, inflammatory bowel disease, chronic atrophic gastritis are evaluated as potential pathogenetic mechanisms. Consistent evidence is available regarding sporadic gastric NENs and MEN1 related duodenopancreatic NENs precursor lesions, and genetic-epigenetic mutations may play a pivotal role in tumor development and bone metastases onset. In lung neuroendocrine tumors (NETs), diffuse proliferation of neuroendocrine cells on the bronchial wall (DIPNECH) has been proposed as a premalignant lesion, while in lung neuroendocrine carcinoma nicotine and smoke could be responsible for carcinogenic processes. Also, rare primary NENs such as thymic (T-NENs) and Merkel cell carcinoma (MCC) have been analyzed, finding different possible pathogenetic mechanisms. EXPERT OPINION New technologies in genomics and epigenomics are bringing new light to the pathogenetic landscape of NENs, but further studies are needed to improve both prevention and treatment in these heterogeneous neoplasms.
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Affiliation(s)
- Roberta Modica
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
| | - Alessia Liccardi
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
| | - Roberto Minotta
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
| | - Giuseppe Cannavale
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
| | - Elio Benevento
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
| | - Annamaria Colao
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Napoli, Italy
- UNESCO Chair "Education for Health and Sustainable Development, " Federico II University, Naples, Italy
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Ricco G, Seminerio R, Andrini E, Malvi D, Gruppioni E, Altimari A, Zagnoni S, Campana D, Lamberti G. BRAF V600E-mutated large cell neuroendocrine carcinoma responding to targeted therapy: a case report and review of the literature. Anticancer Drugs 2023; 34:1076-1084. [PMID: 36847048 DOI: 10.1097/cad.0000000000001508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine tumor, commonly arising in the lung or in the gastrointestinal tract, with a frequent proportion of unknown primary origin (20%). In the metastatic setting, platinum-based or fluoropyrimidine-based chemotherapeutic regimens are as considered the first-line treatment, despite the limited duration of response. To date, the prognosis of advanced high-grade neuroendocrine carcinoma remains poor, suggesting the need to explore new treatment strategies in this orphan tumor. The evolving molecular landscape of LCNEC, not yet been completely defined, could explain the heterogeneous response to different chemotherapeutic regimens and suggest that treatment strategy could be driven by molecular features. v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, well described in melanoma, thyroid cancer, colon cancer and lung adenocarcinoma, account for approximately 2% of cases in lung LCNEC. Here, we describe the case of a patient with a BRAF V600E-mutated LCNEC of unknown primary origin who partially responded to BRAF/mitogen-activated protein kinase kinase inhibitors after standard treatment. Additionally, BRAF V600E circulating tumor DNA was used to monitor disease response. Thereafter, we reviewed the available literature about the role of targeted therapy in high-grade neuroendocrine neoplasms to provide insight for future research to identify patients with driver oncogenic mutations, who can potentially benefit from target therapy.
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Affiliation(s)
- Gianluca Ricco
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi University Hospital, ENETS Center of Excellence
| | - Renata Seminerio
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi University Hospital, ENETS Center of Excellence
| | - Elisa Andrini
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi University Hospital, ENETS Center of Excellence
| | - Deborah Malvi
- Division of Pathology, Azienda Ospedaliero-Universitaria di Bologna
| | - Elisa Gruppioni
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Annalisa Altimari
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Stefano Zagnoni
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Davide Campana
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi University Hospital, ENETS Center of Excellence
| | - Giuseppe Lamberti
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi University Hospital, ENETS Center of Excellence
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Viel G, Ciarleglio FA, Frisini M, Marcucci S, Valcanover S, Bragantini E, Barbareschi M, Mereu L, Tateo S, Merola E, Armelao F, De Pretis G, Brolese M, Decarli NL, Brolese A. Appendiceal collision tumors: case reports, management and literature review. Front Surg 2023; 10:1184322. [PMID: 37351326 PMCID: PMC10282651 DOI: 10.3389/fsurg.2023.1184322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/10/2023] [Indexed: 06/24/2023] Open
Abstract
Appendiceal tumors are incidentally detected in 0.5% cases of appendectomy for acute appendicitis and occur in approximately 1% of all appendectomies. Here, we report two cases of appendiceal collision tumors in two asymptomatic women. In both cases, imaging revealed right-lower-quadrant abdominal masses, which were laparoscopically resected. In both cases, histological examinations revealed an appendiceal collision tumor comprising a low-grade appendiceal mucinous neoplasm and well-differentiated neuroendocrine neoplasm (NEN). For complete oncological control, right hemicolectomy was performed in one patient for the aggressive behavior of NEN; however, histology revealed no metastasis. The other patient only underwent appendectomy. No further treatment was recommended. According to the latest guidelines, exact pathology needs to be defined. Proper management indicated by a multidisciplinary team is fundamental.
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Affiliation(s)
- Giovanni Viel
- Department of Surgery, Hepato-Biliary Surgery Unit, Santa Chiara Hospital, Trento, Italy
| | | | - Marco Frisini
- Department of Surgery, Hepato-Biliary Surgery Unit, Santa Chiara Hospital, Trento, Italy
| | - Stefano Marcucci
- Department of Surgery, Hepato-Biliary Surgery Unit, Santa Chiara Hospital, Trento, Italy
| | - Stefano Valcanover
- Department of Surgery, Hepato-Biliary Surgery Unit, Santa Chiara Hospital, Trento, Italy
| | - Emma Bragantini
- Pathology Unit, Department of Clinical Services, Santa Chiara Hospital, Trento, Italy
| | - Mattia Barbareschi
- Pathology Unit, Department of Clinical Services, Santa Chiara Hospital, Trento, Italy
| | - Liliana Mereu
- Department of Obstetrics and Gynecology, Santa Chiara Hospital, Trento, Italy
| | - Saverio Tateo
- Department of Obstetrics and Gynecology, Santa Chiara Hospital, Trento, Italy
| | - Elettra Merola
- Department of Gastroenterology, Santa Chiara Hospital, Trento, Italy
| | - Franco Armelao
- Department of Gastroenterology, Santa Chiara Hospital, Trento, Italy
| | | | - Marco Brolese
- Hepatobiliary and Liver Transplant Unit, University of Padua School of Medicine, Padua, Italy
| | - Nicola L. Decarli
- Pathology Unit, Department of Clinical Services, Santa Chiara Hospital, Trento, Italy
| | - Alberto Brolese
- Department of Surgery, Hepato-Biliary Surgery Unit, Santa Chiara Hospital, Trento, Italy
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Henzinger H, Brcic I. From morphology to molecular targets—the pathologist’s view in diagnosing gastroenteropancreatic neuroendocrine neoplasms. MEMO - MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2022; 15:287-293. [DOI: 10.1007/s12254-022-00850-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/05/2022] [Indexed: 12/12/2022]
Abstract
SummaryIn the last decade, a number of genetic alterations in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have been identified. In addition, differences in tumor morphology as well as proliferation index (Ki-67) or number of mitoses have led to changes in the classification of these neoplasms. According to the new World Health Organization (WHO) classification, GEP-NENs are now divided into two genetically and prognostically different categories: (i) well-differentiated neuroendocrine tumors (NET) subdivided into low (G1), intermediate (2) and high (G3) grade tumors, and (ii) poorly differentiated neuroendocrine carcinomas (NEC). In addition, a group of mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN) has been defined. This review focuses on the clinical, morphological, immunohistochemical and molecular findings of the GEP-NENs and their key diagnostic features that can help the pathologist to differentiate between tumors in this heterogeneous group. In challenging cases, additional immunohistochemical and/or molecular analysis can be helpful to determine the correct diagnosis and proper treatment for the patient.
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A rare case of poorly differentiated mixed neuroendocrine-nonneuroendocrine tumor of the caecum with long term survival: A case report. Endocr Regul 2022; 56:249-253. [DOI: 10.2478/enr-2022-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Abstract
A 59-year-old woman presented with flushing attacks accompanied by tachycardia and hypotension, which lasted approximately 30 to 60 minutes, underwent 18 years ago a gastrointestinal tumor resection. The histologic examination revealed a poorly differentiated mixed neuroendocrine/adenocarcinoma located in the caecum with regional metastases. Postoperatively, the patient received combined chemotherapy of 5-fluorouracil with interferon for six months and since has remained asymptomatic. Her examination revealed positivity for chromogranin A (CgA) and a-Fetoprotein (aFP) (580 ng/24 h, normal range 27–94, and 10 IU/mL, normal range 0–6, respectively). Urinary 5-hydroxy indole acetic acid excretion was remarkably high (41.8 mg/24 h, normal range 2–10 mg/24 h). An abdominal Magnetic Resonance Imaging scan revealed multiple focal loci in the liver whose histological examination revealed a carcinoid tumor confirmed by an Octreoscan. Additional uptake was noted on the right shoulder and the right sternum-clavicle joint confirmed by Tc-99m MDP scan. The patient received somatostatin analogue therapy followed by long-acting release octreotide analogue therapy (30 mg/month) showing a partial improvement of relevant biomarkers. Two years later, carcinoid syndrome symptoms reappeared and due to the tumors expression of somatostatin receptors the patient received peptide receptor radionuclide therapy with 177Lu-DOTATATE that resulted in both clinical and biochemical improvements.
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7
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Biancotti R, Dal Pozzo CA, Parente P, Businello G, Angerilli V, Realdon S, Savarino EV, Farinati F, Milanetto AC, Pasquali C, Vettor R, Grillo F, Pennelli G, Luchini C, Mastracci L, Vanoli A, Milione M, Galuppini F, Fassan M. Histopathological Landscape of Precursor Lesions of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms. Dig Dis 2022; 41:34-48. [PMID: 35816999 DOI: 10.1159/000525421] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 05/12/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Despite the important advances in research on neuroendocrine neoplasms of the gastro-entero-pancreatic tract, their precursor lesions are much less well known. SUMMARY This review analyzes the preneoplastic neuroendocrine lesions of the gastro-entero-pancreatic tract, by adopting a coherent anatomical benchmark. In particular, the settings in which neuroendocrine precursor lesions represent well-recognized pathophysiological and morphological entities (with eventual molecular correlates) have been distinguished from the ones in which the nature of preneoplastic changes is still obscure. KEY MESSAGES The aim of the paper was to summarize what is known about precursor lesions of gastro-entero-pancreatic neuroendocrine tumors, with the goal of providing a useful tool for future research aimed at obtaining a fuller understanding of the underlying biology and early development of these diseases.
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Affiliation(s)
- Rachele Biancotti
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Edoardo Vincenzo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabio Farinati
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Anna Caterina Milanetto
- Division of Surgery, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Claudio Pasquali
- Division of Surgery, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Roberto Vettor
- Endocrine-Metabolic Laboratory, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Center for the Study and the Integrated Management of Obesity, Padua University Hospital, Padua, Italy
| | - Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Genova, Italy
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Gianmaria Pennelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Genova, Italy
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Galuppini
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
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Prisciandaro M, Antista M, Raimondi A, Corti F, Morano F, Centonze G, Sabella G, Mangogna A, Randon G, Pagani F, Prinzi N, Niger M, Corallo S, Castiglioni di Caronno E, Massafra M, Bartolomeo MD, de Braud F, Milione M, Pusceddu S. Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective. Front Oncol 2022; 12:780716. [PMID: 35186729 PMCID: PMC8856722 DOI: 10.3389/fonc.2022.780716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/10/2022] [Indexed: 11/26/2022] Open
Abstract
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
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Affiliation(s)
- Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- *Correspondence: Michele Prisciandaro,
| | - Maria Antista
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Corti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
| | - Giovanni Randon
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pagani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Marco Massafra
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Massimo Milione
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Shi M, Fan Z, Xu J, Yang J, Li Y, Gao C, Su P, Wang X, Zhan H. Gastroenteropancreatic neuroendocrine neoplasms G3: Novel insights and unmet needs. Biochim Biophys Acta Rev Cancer 2021; 1876:188637. [PMID: 34678439 DOI: 10.1016/j.bbcan.2021.188637] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/30/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022]
Abstract
According to the 2019 WHO pathology grading system, high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) can be divided into well differentiated neuroendocrine tumors G3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). GEP-NETs G3 and GEP-NECs present significant differences in driver genes and disease origin. NETs G3 and NECs have been confirmed to be two distinct diseases with different genetic backgrounds, however, this issue remains controversial. The prognosis of NETs G3 is significantly better than that of NECs. The differential diagnosis of GEP-NETs G3 and GEP-NECs should be combined with the patient's medical history, tumor histopathology, Ki-67 index, DAXX/ATRX, TP53 and Rb expression as well as other immunohistochemical indicators. In addition, the treatment strategies of these two subgroups are very different. Here, we summarize recent findings focused on the genomics, clinical manifestations, diagnosis, treatment and other aspects of high-grade GEP-NENs (G3). This review may help further our understanding of the carcinogenesis, diagnosis and treatment of GEP-NENs G3.
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Affiliation(s)
- Ming Shi
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Jianwei Xu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Jian Yang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Yongzheng Li
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Changhao Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Peng Su
- Department of Pathology, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Xiao Wang
- Department of Pathology, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China.
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Fassan M, Milione M, Maddalena G, Cremolini C, Schirripa M, Pietrantonio F, Pella N, Dell'Aquila E, Sperti E, Zichi C, Bergamo F, Volante M, Boccaccino A, Morano F, Cortiula F, De Maglio G, Rimassa L, Smiroldo V, Calvetti L, Aprile G, Salvatore L, Santini D, Salmaso R, Centonze G, Biason P, Borga C, Lonardi S, Zagonel V, Dei Tos AP, Di Maio M, Loupakis F. Synaptophysin expression in V600EBRAF-mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis. Eur J Cancer 2021; 146:145-154. [PMID: 33607478 DOI: 10.1016/j.ejca.2021.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/29/2020] [Accepted: 01/10/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. METHODS We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests. RESULTS Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001). CONCLUSIONS Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
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Affiliation(s)
- Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.
| | - Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giulia Maddalena
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Marta Schirripa
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Nicoletta Pella
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Emanuela Dell'Aquila
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Elisa Sperti
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Francesca Bergamo
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Marco Volante
- Department of Oncology, University of Turin at San Luigi Hospital, Orbassano (TO), Italy
| | - Alessandra Boccaccino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Cortiula
- Department of Oncology, University and General Hospital, Udine, Italy; Department of Medicine (DAME), University of Udine, Italy
| | | | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Valeria Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Lorenzo Calvetti
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | - Lisa Salvatore
- U.O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Roberta Salmaso
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giovanni Centonze
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Paola Biason
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Chiara Borga
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Sara Lonardi
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Vittorina Zagonel
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Angelo P Dei Tos
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Fotios Loupakis
- Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
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11
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Tamura N, Honma Y, Sekine S, Tsukamoto S, Hirano H, Okita N, Shoji H, Iwasa S, Takashima A, Kato K, Boku N. Case report: potential treatment of metastatic amphicrine carcinoma of the rectum with FOLFOXIRI chemotherapy. Oxf Med Case Reports 2020; 2020:omaa097. [PMID: 33269082 PMCID: PMC7685017 DOI: 10.1093/omcr/omaa097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/14/2020] [Accepted: 09/06/2020] [Indexed: 11/14/2022] Open
Abstract
Amphicrine carcinoma (AmC) is a unique epithelial tumor displaying exocrine and endocrine features in the same cell. It shows an adenocarcinoma-like cellular form and has endocrine granules. There are few reports describing chemotherapy for AmC. Here, we describe a case with metastatic AmC from the rectum that was treated with FOLFOXIRI chemotherapy. A 64-year-old man was diagnosed with a submucosal lesion on the scar produced after an endoscopic mucosal resection, which had been performed for adenocarcinoma of the rectum 2 years before. The endoscopic submucosal dissection revealed AmC. The abdominoperineal resection including lymph nodes dissection was performed. Thereafter, computed tomography showed multiple liver metastases, and FOLFOXIRI was administered. The best overall response was partial response, and progression-free survival was 8.7 months. After 16.0 months since first-line chemotherapy the patient died. We can therefore conclude that FOLFOXIRI may be effective for AmC of the rectum.
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Affiliation(s)
- Nobumasa Tamura
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshitaka Honma
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Shigeki Sekine
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Shunsuke Tsukamoto
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Hidekazu Hirano
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Natsuko Okita
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Shoji
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Satoru Iwasa
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Atsuo Takashima
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Narikazu Boku
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
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12
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Genetic Characteristics of Colorectal Neuroendocrine Carcinoma: More Similar to Colorectal Adenocarcinoma. Clin Colorectal Cancer 2020; 20:177-185.e13. [PMID: 33041225 DOI: 10.1016/j.clcc.2020.09.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite the increasing incidence rate of colorectal neuroendocrine carcinoma (CR-NEC), there are still few sequencing data to depict the genomic characteristics of CR-NEC. PATIENTS AND METHODS Next-generation sequencing data of CR-NEC, colorectal adenocarcinoma (COREAD), lung neuroendocrine carcinoma (lung NEC), and gastrointestinal neuroendocrine tumor (GI-NET) were retrieved from the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) database platform. Overall survival data of patients were obtained from cBioPortal. RESULTS The median tumor mutation burden (TMB) was 5.18 per megabase. TP53 (65.5%), APC (59.5%), KRAS (36.9%), BRAF (20.2%), and RB1 (16.7%) were the most common genes harboring somatic mutations. Nearly all of the BRAF mutations (88.2%) caused V600E. The most common copy number alterations were gain of MYC (12.3%), loss of RB1 (10.7%), and loss of PTEN (5.4%). Compared to lung NEC and GI-NET, the genetic characteristics of CR-NEC were more similar to that of COREAD. CR-NEC had a higher rate of potentially targetable gene alterations compared to lung NEC and GI-NET, and BRAFV600E might be a promising treatment target. Survival analysis indicated that patients with high TMB had significantly worse survival than patients with low TMB (P < .001). In addition, KRAS and RB1 alteration were found to be correlated with worse survival (both P = .023). CONCLUSION CR-NEC has genetic alterations that are more similar to COREAD than other entities. A substantial group of CR-NEC harboring potentially targetable alterations (BRAFV600E) deserves to be tested in clinical practice.
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13
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Chen J, Wang A, Ji K, Bu Z, Ji J. Comparison of overall survival of gastric neoplasms containing neuroendocrine carcinoma components with gastric adenocarcinoma: a propensity score matching study. BMC Cancer 2020; 20:777. [PMID: 32811471 PMCID: PMC7437076 DOI: 10.1186/s12885-020-07281-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/09/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Gastric neoplasms containing neuroendocrine carcinoma (NEC) components are rare malignancies with highly aggressive behavior and a poor prognosis and include pure NEC and mixed tumors containing NEC components. We aimed to investigate whether there is a distinct difference in overall survival (OS) between gastric neoplasms containing NEC components and gastric adenocarcinoma. METHODS Surgically resected gastric neoplasms containing NEC components (n = 180) and gastric adenocarcinomas (n = 785) from January 2013 to December 2019 at Peking University Cancer Hospital were retrospectively analysed. Patients were categorized into a surgical group and a neoadjuvant group and adjusted using propensity score matching. In the two groups, gastric neoplasms containing NEC components were divided into pure NEC and mixed tumors with less than 30% (< 30% G-HMiNEN), between 30 and 70% (G-HMiNEN) and more than 70% (> 70% G-HMiNEN) neuroendocrine carcinoma components. OS was compared between these groups and the gastric adenocarcinoma group. RESULTS The OS of gastric neoplasms containing neuroendocrine NEC components was poorer than that of gastric adenocarcinomas in the surgical group, regardless of whether the percentage of neuroendocrine cancer components was less than 30%, between 30 and 70%, more than 70% or 100%. Cox multivariable regression analysis suggested that tumor category (neoplasms containing NEC components or gastric adenocarcinoma) was an independent risk factor for prognosis. Interestingly, among patients receiving neoadjuvant therapy, the difference was not significant. CONCLUSIONS Gastric neoplasms containing any proportion of NEC components had poorer overall survival than gastric adenocarcinoma in patients treated with surgery directly, indicating that these neoplasms are more malignant than gastric adenocarcinoma. Among the patients receiving neoadjuvant therapy, the difference in overall survival was not significant, which was in sharp contrast with the results of the surgery group, suggesting that neoadjuvant therapy may have a good effect in the treatment of these neoplasms.
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Affiliation(s)
- Jiahui Chen
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Ke Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Zhaode Bu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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14
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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15
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Chen X, Wang X, Abadi M, Kumar A. Colorectal Large-Cell Neuroendocrine Carcinoma: Case Report and Literature Review for Potential Novel Therapeutic Options. Clin Colorectal Cancer 2019; 19:61-64. [PMID: 31761668 DOI: 10.1016/j.clcc.2019.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/20/2019] [Accepted: 10/16/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Xiaoyi Chen
- Department of Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY
| | - Xiaoyang Wang
- Department of Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY
| | - Maria Abadi
- Department of Pathology, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY
| | - Abhishek Kumar
- Department of Hematology/Oncology, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY.
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16
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von Arx C, Capozzi M, López-Jiménez E, Ottaiano A, Tatangelo F, Di Mauro A, Nasti G, Tornesello ML, Tafuto S. Updates on the Role of Molecular Alterations and NOTCH Signalling in the Development of Neuroendocrine Neoplasms. J Clin Med 2019; 8:1277. [PMID: 31443481 PMCID: PMC6780206 DOI: 10.3390/jcm8091277] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/13/2019] [Accepted: 08/20/2019] [Indexed: 12/17/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required.
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Affiliation(s)
- Claudia von Arx
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione "G. Pascale", 80131 Naples, Italy
- Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK
| | - Monica Capozzi
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione "G. Pascale", 80131 Naples, Italy
| | - Elena López-Jiménez
- Cancer Cell Metabolism Group. Centre for Haematology, Immunology and Inflammation Department, Imperial College London, London W12 0HS, UK
| | - Alessandro Ottaiano
- SSD Innovative Therapies for Abdominal Metastases-Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori, IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy
| | - Annabella Di Mauro
- Department of Pathology, Istituto Nazionale Tumori, IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy
| | - Guglielmo Nasti
- SSD Innovative Therapies for Abdominal Metastases-Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS-Fondazione "G. Pascale", 80131 Naples, Italy
| | - Maria Lina Tornesello
- Unit of Molecular Biology and Viral Oncology, Department of Research, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy.
| | - Salvatore Tafuto
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione "G. Pascale", 80131 Naples, Italy.
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17
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Ogimi T, Sadahiro S, Kamei Y, Chan LF, Miyakita H, Saito G, Okada K, Suzuki T, Kajiwara H. Distribution of Neuroendocrine Marker-Positive Cells in Colorectal Cancer Tissue and Normal Mucosal Tissue: Consideration of Histogenesis of Neuroendocrine Cancer. Oncology 2019; 97:294-300. [PMID: 31390635 DOI: 10.1159/000501521] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 06/17/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Colorectal neuroendocrine carcinoma (NEC) is a rare disease, and mixed cases with colorectal adenocarcinoma also exist. The histogenesis of this disease remains unclear. We studied the numbers of neuroendocrine marker-positive cells in adenocarcinoma tissue and in normal -mucosal tissue to investigate the relation between adenocarcinoma and NEC and to discuss the histogenesis of NEC. METHODS We studied a total of 354 curatively resected cases of stage II or III colon cancer and 36 cases of rectal cancer treated at the Tokai University Hospital between 2007 and 2012. Adenocarcinoma tissue and normal mucosal tissue were immunohistochemically stained with chromogranin A, synaptophysin, and CD56. Cases in which neuroendocrine marker-positive cells were found in cancer tissue were defined as positive. In normal mucosa, the numbers of positive cells per 15 high-power fields (HPF) were counted. RESULTS Among the 390 cases, 181 cases had right sided colon cancer, 173 cases had left sided colon cancer, and 36 cases had rectal cancer. The rates of positive staining for chromogranin A, synaptophysin, and CD56 were significantly higher in the right sided colon than in the left sided colon, consistent with the preferred sites of NEC as reported previously. Cells positive for chromogranin A and synaptophysin in normal mucosa were significantly more common in the rectum and the left sided colon than in the right sided colon. No site-specific differences were found for CD56. CONCLUSIONS Neuroendocrine marker-positive cells in colorectal cancer tissue are more common in the right sided colon, whereas neuroendocrine marker-positive cells in normal mucosa are more common in the rectum. These results suggest that NEC may arise from preceding adenocarcinomas.
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Affiliation(s)
- Takashi Ogimi
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Sotaro Sadahiro
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan,
| | - Yutaro Kamei
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Lin Fung Chan
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Hiroshi Miyakita
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Gota Saito
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Kazutake Okada
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Toshiyuki Suzuki
- Department of Surgery, Tokai University, School of Medicine, Isehara, Japan
| | - Hiroshi Kajiwara
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
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18
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Mafficini A, Scarpa A. Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 2019; 40:506-536. [PMID: 30657883 PMCID: PMC6534496 DOI: 10.1210/er.2018-00160] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
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Affiliation(s)
- Andrea Mafficini
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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19
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Sato O, Tsuchikawa T, Yamada T, Sato D, Nakanishi Y, Asano T, Noji T, Yo K, Ebihara Y, Murakami S, Nakamura T, Okamura K, Shichinohe T, Mitsuhashi T, Hirano S. Metastatic mixed adenoneuroendocrine carcinoma of the liver successfully resected by hepatic trisectionectomy following chemotherapy: A case report. Clin Case Rep 2019; 7:491-496. [PMID: 30899479 PMCID: PMC6406150 DOI: 10.1002/ccr3.1968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/20/2018] [Accepted: 11/23/2018] [Indexed: 12/25/2022] Open
Abstract
The chemotherapy guidelines for mixed adenoneuroendocrine carcinoma (MANEC) remain poorly defined, and prognosis remains dismal. In this case, we successfully performed resection after FOLFOX for unresectable metastatic MANEC of the liver. Thus, chemotherapy for adenocarcinoma may be effective for MANEC.
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Affiliation(s)
- Osamu Sato
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Toru Yamada
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Daisuke Sato
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Takehiro Noji
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Kurashima Yo
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Yuma Ebihara
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Soichi Murakami
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Toru Nakamura
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
| | - Tomoko Mitsuhashi
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery IIHokkaido University Faculty of MedicineSapporoJapan
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20
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Yanagihara K, Kubo T, Mihara K, Kuwata T, Ochiai A, Seyama T, Yokozaki H. Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma. Oncotarget 2018; 9:36503-36514. [PMID: 30559933 PMCID: PMC6284856 DOI: 10.18632/oncotarget.26367] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022] Open
Abstract
Poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC) is a rare cancer with poor prognosis. However, a D-NEC cell line has not yet been established to study the disease. We established a cell line, TCC-NECT-2, from the ascites tumor of a 59-year-old male Japanese patient with D-NEC. TCC-NECT-2 was positive for neuroendocrine markers, chromogranin A (CGA), cluster of differentiation 56 (CD56/NCAM), synaptophysin (SYN/p38), and neuron specific enolase (NSE). Cells exhibited retinoblastoma (RB) protein loss. Orthotopic implantation of TCC-NECT-2 cells into nu/nu mice resulted in tumor formation (incidence = 83.3%) with neuroendocrine characteristics, metastasis, and weight loss. BRAFV600E and TP53 mutations and C-MYC gene amplification were also observed in TCC-NECT-2. BRAFV600E-expressing TCC-NECT-2 cells were sensitive to BRAF inhibitor vemurafenib, and especially dabrafenib, in vitro, and were strongly inhibited in a dose-dependent manner. Dabrafenib treatment (30 mg/kg) in a xenograft model for 14 days significantly suppressed tumor growth (percent tumor growth inhibition, TGI% = 48.04). An enhanced therapeutic effect (TGI% = 95.81) was observed on combined treatment of dabrafenib and irinotecan (40 mg/kg). Therefore, TCC-NECT-2, the first reported cell line derived from D-NEC, might serve as a useful model to study the basic biology of D-NEC and translational applications for treatment.
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Affiliation(s)
- Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan.,Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takanori Kubo
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Keichiro Mihara
- Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan
| | - Atsushi Ochiai
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Toshio Seyama
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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21
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Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, Anlauf M, Schott M, Göring W, Esposito I, Stoecklein NH, Knoefel WT, Krieg A. BRAF V600E mutation: A promising target in colorectal neuroendocrine carcinoma. Int J Cancer 2018; 144:1379-1390. [PMID: 30144031 DOI: 10.1002/ijc.31828] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 07/04/2018] [Accepted: 08/02/2018] [Indexed: 12/16/2022]
Abstract
To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.
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Affiliation(s)
- Levent Dizdar
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Thomas A Werner
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Jasmin C Drusenheimer
- Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Birte Möhlendick
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Katharina Raba
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Inga Boeck
- Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany
| | - Martin Anlauf
- Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany
| | - Matthias Schott
- Division for Specific Endocrinology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Wolfgang Göring
- Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Nikolas H Stoecklein
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Wolfram T Knoefel
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
| | - Andreas Krieg
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
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22
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Gock M, Mullins CS, Harnack C, Prall F, Ramer R, Göder A, Krämer OH, Klar E, Linnebacher M. Establishment, functional and genetic characterization of a colon derived large cell neuroendocrine carcinoma cell line. World J Gastroenterol 2018; 24:3749-3759. [PMID: 30197480 PMCID: PMC6127660 DOI: 10.3748/wjg.v24.i33.3749] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 06/14/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To establish cell line and patient-derived xenograft (PDX) models for neuroendocrine carcinomas (NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research including biomarker testing and drug response prediction. METHODS Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue (HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting (i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid cancers. RESULTS The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a CpG island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS (wt), BRAF (mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUSION We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.
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MESH Headings
- Adult
- Animals
- Antineoplastic Agents/pharmacology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Large Cell/genetics
- Carcinoma, Large Cell/pathology
- Carcinoma, Large Cell/surgery
- Carcinoma, Neuroendocrine/genetics
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/surgery
- Cell Culture Techniques/methods
- Cell Line, Tumor/drug effects
- Cell Line, Tumor/metabolism
- Cell Line, Tumor/pathology
- Cell Movement/genetics
- Colon/pathology
- Colon/surgery
- CpG Islands/genetics
- DNA Fingerprinting
- DNA Methylation/genetics
- DNA Mutational Analysis
- Drug Resistance, Neoplasm/genetics
- Female
- Flow Cytometry
- Humans
- Mice
- Mice, Nude
- Mutation
- Neoplasm Invasiveness/genetics
- Neoplasm Invasiveness/pathology
- Primary Cell Culture
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Michael Gock
- Department of General Surgery, University of Rostock, Rostock 18055, Germany
| | - Christina S Mullins
- Department of General Surgery, Section of Molecular Oncology and Immunotherapy, University of Rostock, Rostock 18055, Germany
| | - Christine Harnack
- Department of General Surgery, Section of Molecular Oncology and Immunotherapy, University of Rostock, Rostock 18055, Germany
| | - Friedrich Prall
- Institute of Pathology, University of Rostock, Rostock 18055, Germany
| | - Robert Ramer
- Institute of Pharmacology, University of Rostock, Rostock 18055, Germany
| | - Anja Göder
- Institute of Toxicology, University Medical Center Mainz, Mainz 55131, Germany
| | - Oliver H Krämer
- Institute of Toxicology, University Medical Center Mainz, Mainz 55131, Germany
| | - Ernst Klar
- Department of General Surgery, University of Rostock, Rostock 18055, Germany
| | - Michael Linnebacher
- Department of General Surgery, Section of Molecular Oncology and Immunotherapy, University of Rostock, Rostock 18055, Germany
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23
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Sorbye H, Baudin E, Perren A. The Problem of High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Beyond. Endocrinol Metab Clin North Am 2018; 47:683-698. [PMID: 30098724 DOI: 10.1016/j.ecl.2018.05.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
High-grade gastroenteropancreatic neuroendocrine neoplasms are well-differentiated neuroendocrine tumors or poorly differentiated small/large cell neuroendocrine carcinoma. Distinguishing these entities relies on different genetic backgrounds and resulting different biology. The new classification creates several problems. Almost all clinical treatment data on neuroendocrine neoplasms do not stratify between well and poorly differentiated, providing insufficient help in treatment selection. Treatment of gastroenteropancreatic neuroendocrine neoplasms should separate between well-differentiated neuroendocrine tumors and neuroendocrine carcinoma, and depends on primary tumor site, stage, proliferation rate, and clinical course. This article addresses how to diagnose and treat gastroenteropancreatic neuroendocrine neoplasms, focusing on well-differentiated neuroendocrine tumors versus neuroendocrine carcinomas.
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Affiliation(s)
- Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway; Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway.
| | - Eric Baudin
- Endocrine Oncology, Gustave Roussy, rue Édouard-Vaillant 114, Villejuif 94800, France
| | - Aurel Perren
- Department of Pathology, University of Bern, Murtenstrasse 31, Bern 3008, Switzerland
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24
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Idrees K, Padmanabhan C, Liu E, Guo Y, Gonzalez RS, Berlin J, Dahlman KB, Beauchamp RD, Shi C. Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma. J Surg Oncol 2018; 117:284-289. [PMID: 28940307 DOI: 10.1002/jso.24834] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 08/17/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND OBJECTIVES The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease. METHODS We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15. RESULTS We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs. CONCLUSION Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.
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Affiliation(s)
- Kamran Idrees
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.,Division of Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Eric Liu
- Rocky Mountain Cancer Centers, Denver, Colorado
| | - Yan Guo
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee
| | - Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York
| | - Jordan Berlin
- Department of Medicine (Hematology/Oncology), Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kimberly B Dahlman
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee
| | - R Daniel Beauchamp
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.,Division of Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee
| | - Chanjuan Shi
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
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25
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Schizas D, Michalinos A, Alexandrou P, Moris D, Baliou E, Tsilimigras D, Throupis T, Liakakos T. A unique tripartite collision tumor of the esophagus: A case report. Medicine (Baltimore) 2017; 96:e8784. [PMID: 29245236 PMCID: PMC5728851 DOI: 10.1097/md.0000000000008784] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 10/27/2017] [Accepted: 10/27/2017] [Indexed: 12/30/2022] Open
Abstract
RATIONALE We report a unique case of a tripartite esophageal collision tumor consisting of three separate histologic types. PATIENTS CONCERNS Therapeutic dilemmas on the proper treatment of those rare neoplasms remain unanswered considering both proper surgical therapy and adjuvant therapy. DIAGNOSE In this paper, we report a unique case of a patient with a tripartite esophageal collision tumor consisting of a small cell carcinoma, an adenocarcinoma of medium differentiation and a signet ring cell carcinoma. Diagnosis is difficult as clinical presentation of the patient was undistinguishable from other, commoner tumor types. INTERVENTIONS The patient's diagnostic and therapeutic course along with available data on the collisions tumor's biological behavior and treatment are briefly discussed. OUTCOMES Esophagectomy is the best treatment options for these patients. Unique nature of this tumor demands aggresive oncologic treatment. LESSONS Collision tumors are rare neoplasms consisting of distinct cell populations developing in juxtaposition to one another without any areas of intermingling. Various cell types can be found. However, collision neoplasms of the esophagus combining adenomatous and neuroendocrine components are exceedingly rare, with only 5 cases described to date in the literature. Given their rarity, limited information is available on their tumorigenesis, biological behavior and clinical course. In general, these tumors are aggressive neoplasms and significantly affect patient treatment and prognosis.
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Affiliation(s)
| | | | - Paraskevi Alexandrou
- Department of Pathology, National and Kapodistrian University of Athens, Athens, Attiki, Greece
| | - Demetrios Moris
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH
| | - Evangelia Baliou
- Department of Pathology, National and Kapodistrian University of Athens, Athens, Attiki, Greece
| | | | - Theodore Throupis
- Department of Anatomy, National and Kapodistrian Athens, Athens, Attiki, Greece
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26
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Scoazec JY, Couvelard A. [Classification of pancreatic neuroendocrine tumours: Changes made in the 2017 WHO classification of tumours of endocrine organs and perspectives for the future]. Ann Pathol 2017; 37:444-456. [PMID: 29169836 DOI: 10.1016/j.annpat.2017.10.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/08/2017] [Indexed: 02/01/2023]
Abstract
The WHO classification of the tumors of endocrine organs, published in July 2017, has introduced significant changes in the classification of pancreatic neuroendocrine tumors, the previous version of which has appeared in 2010, within the WHO classification of the tumors of the digestive system. The main change is the introduction of a new category of well-differentiated neoplasms, neuroendocrine tumors G3, in addition to the previous categories of neuroendocrine tumors G1 and G2. The differential diagnosis between neuroendocrine tumors G3 (well-differentiated) and neuroendocrine carcinomas (poorly-differentiated) might be difficult; the authors of the WHO classification therefore suggest the use of a number of immunohistochemical markers to facilitate the distinction between the two entities. The other changes are: (a) the modification of the threshold between neuroendocrine tumors G1 and G2, now set at 3%; (b) the terminology used for mixed tumors: the previous term mixed adeno-neuroendocrine carcinoma (MANEC) is substituted by the term mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Finally, the recommendations for Ki-67 index evaluation are actualized. Even if these changes only concern, stricto sensu, the neuroendocrine tumors of pancreatic location, they will probably be applied, de facto, for all digestive neuroendocrine tumors. The revision of the histological classification of pancreatic neuroendocrine tumors coincides with the revision of their UICC TNM staging; significant changes have been made in the criteria for T3 and T4 stages. Our professional practices have to take into account all these modifications.
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Affiliation(s)
- Jean-Yves Scoazec
- Département de biologie et pathologie médicales, Gustave-Roussy Cancer Campus, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France; Faculté de médecine de Bicêtre, université Paris Sud, 94270 Le Kremlin-Bicêtre, France.
| | - Anne Couvelard
- DHU Unity, département de pathologie, hôpital Bichat, Assistance publique-Hôpitaux de Paris, 75018 Paris, France; Faculté de médecine Bichat, université Paris Diderot, 75018 Paris, France
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27
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Prendeville S, Al-Bozom I, Compérat E, Sweet J, Evans AJ, Ben-Gashir M, Mete O, van der Kwast TH, Downes MR. Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin? Histopathology 2017; 71:926-933. [DOI: 10.1111/his.13330] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/26/2017] [Indexed: 02/06/2023]
Affiliation(s)
| | | | - Eva Compérat
- Hôpital La Pitié-Salpêtrière; Paris France
- Hôpital Tenon; Paris France
| | - Joan Sweet
- University Health Network; Toronto ON Canada
| | | | | | - Ozgur Mete
- University Health Network; Toronto ON Canada
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28
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Girardi DM, Silva ACB, Rêgo JFM, Coudry RA, Riechelmann RP. Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: A systematic review. Cancer Treat Rev 2017; 56:28-35. [PMID: 28456055 DOI: 10.1016/j.ctrv.2017.04.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/04/2017] [Accepted: 04/05/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive tumors. Their molecular pathogenesis is still largely unknown, and consequently, the best therapeutic management also remains to be determined. We conducted a systematic review on molecular alterations found in gastroenteropancreatic NECs (GEP-NECs) and discuss potential applications of targeted therapies in setting. MATERIALS AND METHODS Systematic review of studies about molecular features in tumor tissues of patients with GEP-NECs. The Medline, Lilacs, Embase, Cochrane, Scopus and Opengrey databases were sought, without time, study design or language restrictions. RESULTS Of the 1.564 studies retrieved, 41 were eligible: 33 were retrospective studies and eight were case reports. The studies spanned the years 1997-2017 and involved mostly colorectal, stomach and pancreas primary tumors. Molecular alterations in the TP53 gene and the p53 protein expression were the most commonly observed, regardless of the primary site. Other consistently found molecular alterations were microsatellite instability (MSI) in approximately 10% of gastric and colorectal NEC, and altered signaling cascades of p16/Rb/cyclin D1, Hedgehog and Notch pathways, and somatic mutations in KRAS, BRAF, RB1 and Bcl2. In studies of mixed adeno-neuroendocrine carcinomas (MANECs) the molecular features of GEP-NEC largely resemble their carcinoma/adenocarcinomas tumor counterparts. CONCLUSIONS Despite the paucity of data about the molecular drivers associated with GEP-NEC, some alterations may be potentially targeted with new cancer-directed therapies. Collaborative clinical trials for patients with advanced GEP-NEC are urgently needed.
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Affiliation(s)
- Daniel M Girardi
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
| | - Andrea C B Silva
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
| | - Juliana Florinda M Rêgo
- Unit of Oncology and Hematology, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte, Rio Grande do Norte, Brazil.
| | | | - Rachel P Riechelmann
- Discipline of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil; Oncology Center, Hospital Sírio Libanês, São Paulo, Brazil.
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29
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Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol 2017; 30:610-619. [PMID: 28059096 DOI: 10.1038/modpathol.2016.220] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/07/2016] [Accepted: 11/08/2016] [Indexed: 02/07/2023]
Abstract
Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.
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30
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Woischke C, Schaaf CW, Yang HM, Vieth M, Veits L, Geddert H, Märkl B, Stömmer P, Schaeffer DF, Frölich M, Blum H, Vosberg S, Greif PA, Jung A, Kirchner T, Horst D. In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components. Mod Pathol 2017; 30:95-103. [PMID: 27586204 DOI: 10.1038/modpathol.2016.150] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 12/12/2022]
Abstract
Neuroendocrine carcinomas (NECs) of the colorectum are rare but highly aggressive neoplasms. These tumors show some shared genetic alterations with colorectal adenocarcinomas, and most of them have adjacent glandular adenoma or adenocarcinoma components. However, genetic data on colorectal NECs still are sparse and insufficient for definite conclusions regarding their molecular origin. Based on morphological characterization, panel and whole-exome sequencing, we here present results from an in-depth analysis of a collection of 15 colorectal NECs with glandular components, 10 of which by definition were mixed adenoneuroendocrine carcinomas (MANECs). Among shared genetic alterations of both tumor components, we most frequently found TP53, KRAS and APC mutations that also had highest allele frequencies. Mutations exclusive to glandular or neuroendocrine components outnumbered shared mutations but occurred at lower allele frequencies. Our findings not only provide additional evidence for a common clonal origin of colorectal NECs and adjacent glandular tumor components, but strongly suggest their development through the classical adenoma-carcinoma sequence. Moreover, our data imply early separation of glandular and neuroendocrine components during malignant transformation with subsequent independent mutational evolution.
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Affiliation(s)
- Christine Woischke
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Christian W Schaaf
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Hui-Min Yang
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Michael Vieth
- Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany
| | - Lothar Veits
- Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany
| | - Helene Geddert
- Institut für Pathologie, St Vincentius-Kliniken, Karlsruhe, Germany
| | - Bruno Märkl
- Institut für Pathologie, Klinikum Augsburg, Augsburg, Germany
| | | | - David F Schaeffer
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Matthias Frölich
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Helmut Blum
- Laboratory for Functional Genome Analysis (LAFUGA), at the Gene Center, Ludwig-Maximilians-Universität (LMU), München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Vosberg
- German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Philipp A Greif
- German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Andreas Jung
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas Kirchner
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Horst
- Pathologisches Institut der Ludwig-Maximilians-Universität (LMU), München, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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31
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Ishii N, Araki K, Yokobori T, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Hirai K, Shirabe K, Kuwano H. Presence of Cytokeratin 19-Expressing Cholangiocarcinoma-Like Tumour in a Liver Metastatic Lesion of Rectal Neuroendocrine Tumour. Case Rep Gastroenterol 2016; 10:431-439. [PMID: 27721729 PMCID: PMC5043256 DOI: 10.1159/000446641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/04/2016] [Indexed: 12/12/2022] Open
Abstract
Introduction Tumours with adenocarcinoma and neuroendocrine components have often been reported, although the reason underlying the dual components remains unclear. Case Presentation A 43-year-old woman with multiple liver metastatic lesions of rectal neuroendocrine tumour underwent primary tumour resection and subsequent liver transplantation. Pathological examination indicated a cholangiocarcinoma-like tumour with gland formation, adjacent to a liver metastatic lesion of the neuroendocrine tumour. This tumour comprised atypical columnar epithelium, and stained positively for neuroendocrine markers and the ductal marker cytokeratin 19, indicating amphicrine properties and a partial cholangiocarcinoma phenotype – features not observed in the primary and metastatic neuroendocrine tumours. Conclusion The presence of adenocarcinoma only at the metastatic site indicated that neuroendocrine tumour cells acquired stemness and differentiated into adenocarcinoma through metastasis, or that the adenocarcinoma newly arose from the adjacent epithelium influenced by the neuroendocrine tumour. We propose a novel mechanism for the pathogenesis of mixed tumours in neuroendocrine tumours.
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Affiliation(s)
- Norihiro Ishii
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan; Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Kenichiro Araki
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan; Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Takehiko Yokobori
- Department of Molecular Pharmacology and Oncology, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Mariko Tsukagoshi
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan; Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Takamichi Igarashi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Akira Watanabe
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan; Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norio Kubo
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan; Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Keitaro Hirai
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan
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32
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Smith JD, Nandakumar G. Hindgut Neuroendocrine Neoplasia. Indian J Surg Oncol 2016; 7:73-8. [PMID: 27065686 DOI: 10.1007/s13193-015-0477-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 10/13/2015] [Indexed: 12/17/2022] Open
Abstract
Neuroendocrine neoplasias (NENs) consist of a spectrum of tumors which can originate throughout the body, behave in a variety of different ways but are characterized by a similar histological appearance. This article reviews the classification, staging, diagnosis and treatment of Hindgut Neuroendocrine Neoplasias.
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Affiliation(s)
- James D Smith
- Surgery Weill Cornell Medical College, 525 East 68th Street, New York, NY 10021 USA
| | - Govind Nandakumar
- Courtesy Faculty at Weill Cornell Medical College, 20 Ali Asker Road, 560052 Bangalore, India
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33
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Hammond WA, Crozier JA, Nakhleh RE, Mody K. Genomic profiling of high-grade large-cell neuroendocrine carcinoma of the colon. J Gastrointest Oncol 2016; 7:E22-4. [PMID: 27034803 DOI: 10.3978/j.issn.2078-6891.2015.090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
High-grade neuroendocrine carcinoma (HGNEC) of the colon is a rare and aggressive cancer that has a poor prognosis. Currently no standard treatment exists, and published case series report an overall survival of approximately one year with treatment. Typically patients receive treatment similar to that recommended for small-cell lung cancer, extrapolating from the similarity in cancer biology. Here we report a case of HGNEC of the colon with genomic profiling that identified a KRAS G12D mutation and a PI3K mutation that has not yet been reported in the literature for this tumor type.
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Affiliation(s)
- William A Hammond
- 1 Department of Hematology/Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA ; 2 Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
| | - Jennifer A Crozier
- 1 Department of Hematology/Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA ; 2 Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
| | - Raouf E Nakhleh
- 1 Department of Hematology/Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA ; 2 Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
| | - Kabir Mody
- 1 Department of Hematology/Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA ; 2 Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
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34
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Kleist B, Poetsch M. Neuroendocrine differentiation: The mysterious fellow of colorectal cancer. World J Gastroenterol 2015; 21:11740-11747. [PMID: 26556999 PMCID: PMC4631973 DOI: 10.3748/wjg.v21.i41.11740] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/07/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine differentiation in sporadic colorectal cancer has been recognized since decades, but its clinical impact is still controversially discussed. Detailed parameter analyses hint at the possibility that probably not neuroendocrine differentiation itself, but its association with poor grade of tumor differentiation, lymph node metastases, distant metastases and other unfavorable features contribute to worse clinical outcome. However, other studies deny a relationship between neuroendocrine differentiation and prognosis of colorectal cancer. This review elucidates, whether new insights into the origin of neuroendocrine differentiation in the intestinal epithelium, its regulation by mTOR pathway components and its possible link to the intestinal stem cell compartment could determine a role of neuroendocrine cells as prognostic marker and putative therapeutic target in sporadic colorectal cancer.
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35
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Takizawa N, Ohishi Y, Hirahashi M, Takahashi S, Nakamura K, Tanaka M, Oki E, Takayanagi R, Oda Y. Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor. Hum Pathol 2015; 46:1890-900. [PMID: 26434631 DOI: 10.1016/j.humpath.2015.08.006] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 08/02/2015] [Accepted: 08/13/2015] [Indexed: 12/21/2022]
Abstract
To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, β-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), β-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P < .01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P < .05, respectively) or NETs (10%, 5%, and 5%, P < .01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P < .01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs.
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Affiliation(s)
- Nobuyoshi Takizawa
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Ohishi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Minako Hirahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Shunsuke Takahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masao Tanaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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36
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Nagtegaal ID, Hugen N. The Increasing Relevance of Tumour Histology in Determining Oncological Outcomes in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2015; 11:259-266. [PMID: 26321889 PMCID: PMC4550646 DOI: 10.1007/s11888-015-0280-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer is not just one type of cancer. Differences in outcome and reaction to treatment can at least be partly explained by different histological and molecular subtypes. Recognition of these differences may influence treatment decisions. However, there is huge variation in the amount of information that is available. Several tumour types such as mucinous carcinoma, signet ring cell carcinoma, neuroendocrine carcinoma and adenosquamous carcinoma have such a distinct phenotype that they are readily recognised. However, due to the rarity of signet ring cell carcinoma and adenosquamous carcinoma, limited data are available. More recently defined subtypes, like medullary carcinoma, serrated adenocarcinoma and micropapillary carcinoma, are not adequately diagnosed, which limits research possibilities using large-scale data from registries. In the current review, we systematically describe the histologic subtypes with the clinical and molecular background. We evaluate their prognosis compared to adenocarcinoma not otherwise specified and speculate about the clinical relevance.
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Affiliation(s)
- Iris D Nagtegaal
- Department of Pathology, Radboudumc, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Niek Hugen
- Department of Surgery, Radboudumc, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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37
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Basuroy R, Sarker D, Quaglia A, Srirajaskanthan R, Ramage J. Personalized medicine for gastroenteropancreatic neuroendocrine tumors: a distant dream? INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.15.9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine tumors are heterogeneous cancers that can present with advanced disease. Treatment stratification is often based on limited characterization of tumor behavior from histological grade and imaging assessments. Personalized medicine strategies focus on tailoring therapy through characterization of cancer pathways and the development of biomarkers. This review article explores the current personalized medicine landscape in gastroenteropancreatic neuroendocrine tumors, from tissue and circulating biomarkers development through to tumor heterogeneity and reimbursement issues.
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Affiliation(s)
- Ron Basuroy
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
| | - Debashis Sarker
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Department of Research Oncology, Division of Cancer Studies, King's College London, Strand, WC2R 2LS, UK
| | - Alberto Quaglia
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Histopathology Department, Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rajaventhan Srirajaskanthan
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Gastroenterology Department, University Hospital Lewisham, London, SE13 6LH, UK
| | - John Ramage
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire, RG24 9NA, UK
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38
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Dimmler A, Geddert H, Faller G. EGFR, KRAS, BRAF-mutations and microsatellite instability are absent in goblet cell carcinoids of the appendix. Pathol Res Pract 2014; 210:274-8. [DOI: 10.1016/j.prp.2014.01.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 11/20/2013] [Accepted: 01/13/2014] [Indexed: 02/07/2023]
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39
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Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014; 120:2814-23. [PMID: 24771552 DOI: 10.1002/cncr.28721] [Citation(s) in RCA: 250] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 03/17/2014] [Accepted: 03/19/2014] [Indexed: 12/15/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms are classified as low-grade, intermediate-grade, and high-grade tumors based on morphologic criteria and the proliferation rate. Most studies have been conducted in patients with well differentiated (low-grade to intermediate-grade) neuroendocrine tumors. Data are substantially scarcer on poorly differentiated, high-grade neuroendocrine carcinoma (NEC), which includes the entities of small cell carcinoma and large cell NEC. A literature search of GEP-NEC was performed. Long-term survival was poor even among patients who presented with localized disease. Several studies highlighted heterogeneity within the high-grade NEC category and a need for the further identification of discreet prognostic and predictive groups. Tumors with a Ki-67 proliferation index <55% were less responsive to platinum-based chemotherapy, and patients with such tumors or with well differentiated morphology had better survival than patients who had tumors with poorly differentiated morphology or a higher Ki-67 index. Treatment options beyond platinum-based chemotherapy are emerging. A revision of the World Health Organization high-grade NEC classification seems to be necessary based on recent data. Platinum-based chemotherapy may not be the optimal treatment for patients who have GEP-NEC with a moderately high proliferation rate. Adequate diagnostic and prognostic stratifications constitute the basis for future progress.
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Affiliation(s)
- Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
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40
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Aisner DL, Nguyen TT, Paskulin DD, Le AT, Haney J, Schulte N, Chionh F, Hardingham J, Mariadason J, Tebbutt N, Doebele RC, Weickhardt AJ, Varella-Garcia M. ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res 2013; 12:111-8. [PMID: 24296758 DOI: 10.1158/1541-7786.mcr-13-0479-t] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
UNLABELLED Activated anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases, through gene fusions, have been found in lung adenocarcinomas and are highly sensitive to selective kinase inhibitors. This study aimed at identifying the presence of these rearrangements in human colorectal adenocarcinoma specimens using a 4-target, 4-color break-apart FISH assay to simultaneously determine the genomic status of ALK and ROS1. Among the clinical colorectal cancer specimens analyzed, rearrangement-positive cases for both ALK and ROS1 were observed. The fusion partner for ALK was identified as EML4 and the fusion partner for one of the ROS1-positive cases was SLC34A2, the partner for the other ROS1-positive case remains to be identified. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. In addition, rearrangements were detected in samples that also harbored KRAS and BRAF mutations in two of the three cases. Interestingly, the ALK-positive specimen displayed marked intratumoral heterogeneity and rearrangement was also identified in regions of high-grade dysplasia. Despite the additional oncogenic events and tumor heterogeneity observed, elucidation of the first cases of ROS1 rearrangements and confirmation of ALK rearrangements support further evaluation of these genomic fusions as potential therapeutic targets in colorectal cancer. IMPLICATIONS ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection.
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Affiliation(s)
- Dara L Aisner
- University of Colorado School of Medicine Anschutz Medical Campus, 12801 East 17th Avenue, L18-8118, Mail Stop 8117, Aurora, CO 80045.
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