Neuroendocrine Neoplasia Management : New Approaches for Diagnosis and Treatment

"This book provides the most recent update on the management of neuroendocrine neoplasia (NEN), a term covering all tumors of various organs and/or with a particular histology, including MEN (multiple endocrine neoplasia) related tumors, MiNEN (mixed neuroendocrine-non-neuroendocrine neoplasms), NEC (neuroendocrine carcinoma) and Merkel's carcinoma. NENs are heterogeneous in their biology, clinical presentation and prognosis, showing a great variability in aggressiveness and therapy response. As a result, their treatment is based on a large spectrum of options. The standard therapies are surgery in early disease, various loco-regional procedures in certain conditions and mostly of a palliative nature in metastatic disease. At present, thanks to our increased understanding of molecular signaling pathways, several pharmacological approaches can be used in patients with advanced NENs. Somatostatin analogs display both anti-tumor effects and symptom control. Novel peptide-radio-receptor treatment (PRRT) is used in patients with well differentiated tumors. The agents targeting angiogenesis and/or PI3K/AKT/mTOR pathway, alone or in combination with analogues, have provided encouraging results in advanced disease. The first part of the book focuses on the history, epidemiology and the most relevant scientific achievements, covering the discoveries in genetic and molecular biology, the endoscopic techniques with guided biopsy, and the metabolic imaging with hybrid PET/CT and MRI/CT. It particularly highlights the emerging strategies in therapy, surgery and mini-invasive surgery as well as loco-regional and systemic treatments, including targeted therapy and/or biological therapies. The second part then explores the management of NENs of various anatomical origins and/or with peculiar biology. It describes the range of the current options and the most relevant results from the clinical trials. This informative book provides valuable insights for all those interested in the management of neuroendocrine neoplasia."--Publisher's description Foreword Preface Acknowledgments Contents Part I: Introduction 1: History of Neuroendocrine Neoplasia 1.1 Introduction 1.2 Early History 1.2.1 Carcinoid: The Origin of the Term 1.2.2 Carcinoid Classifications 1.2.3 Clinic History of Carcinoids 1.3 Conclusion References 2: Epidemiology of Neuroendocrine Neoplasms 2.1 Incidence Rate 2.1.1 Neuroendocrine Neoplasms by Age and Gender 2.1.2 Neuroendocrine Neoplasms by Site 2.1.3 Neuroendocrine Neoplasms by Stage 2.2 Incidence Trends 2.3 Neuroendocrine Neoplasms Prevalence 2.4 Neuroendocrine Neoplasms Survival References Part II: Diagnosis 3: New Concepts in Pathology 3.1 Classifications at Present 3.1.1 Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs): World Health Organization (WHO) 2019 Rules (Fig. 3.1a) 3.1.1.1 Current WHO 2019 Classification Classes 3.1.1.2 GEP-NENs Morphological Examination Rules 3.1.1.3 Proliferative Indices: Mitotic Index (MI) and Ki-67 Labeling Index (Ki-67 LI) 3.1.2 Lung Neuroendocrine Neoplasms (LU-NENs) WHO 2015 Rules (Fig. 3.1b) 3.1.3 TNM in GEP- and LU-NENs 3.2 Moving to 2017/2019 GEP Classifications 3.2.1 NET G3 History (Fig. 3.5) 3.2.2 Ki-67 New CutOff (Fig. 3.5) 3.2.3 From MANEC to MiNEN (Figs. 3.6 and 3.7) References 4: Molecular Biology of Neuroendocrine Tumors 4.1 Introduction 4.2 The Lesson from Hereditary Syndromes 4.3 Next-Generation Sequencing Era: The Discovery of Novel Cancer Pathways 4.4 Epigenetic Changes in NETs 4.5 microRNA Deregulation in NETs 4.6 From Single Gene Alteration to Signaling Pathway Perturbations 4.7 Conclusions References 5: Circulating Biochemical Markers of Gastro-Entero-Pancreatic (GEP) Neuroendocrine Neoplasms (NENs) 5.1 Introduction 5.2 Specific Biomarkers 5.2.1 5-Hydroxyindole Acetic Acid (5-HIAA) 5.2.2 Insulin 5.2.3 Gastrin 5.2.4 Vasoactive Intestinal Peptide (VIP) 5.2.5 Glucagon 5.2.6 Somatostatin 5.2.7 Other Circulating Markers 5.2.7.1 Adrenocorticotropic Hormone (ACTH) 5.2.7.2 Corticotropin-Releasing Hormone (CRH) 5.2.7.3 Growth Hormone-Releasing Hormone (GHRH) 5.2.7.4 Calcitonin 5.3 Nonspecific Biomarkers 5.3.1 Chromogranin A (CgA) 5.3.2 Chromogranin B (CgB) 5.3.3 Neuron-Specific Enolase (NSE) 5.3.4 Pancreatic Polypeptide (PP) 5.3.5 Human Chorionic Gonadotropin and Alpha-Fetoprotein 5.4 Novel Circulating Markers 5.4.1 Circulating Tumor Cells (CTC) 5.4.2 miRNA 5.4.3 Circulating Gene Transcripts 5.5 Conclusion References 6: Advances in Diagnostic Imaging 6.1 Introduction on Imaging in NET 6.2 Technical and Technological Aspects 6.2.1 Imaging 6.2.2 Molecular Imaging 6.3 NETs of the Lungs 6.4 GEP NETs 6.4.1 Gastric and Intestinal NETs 6.4.2 Pancreatic NETs 6.5 Conclusion References Part III: New Approaches for Treatment 7: Treatment of NET-Related Symptoms 7.1 Introduction 7.2 Carcinoid Syndrome 7.3 Hypoglycemia 7.4 Zollinger–Ellison Syndrome 7.5 Glucagonoma 7.6 VIPoma 7.7 Somatostatinoma 7.8 Ectopic Syndromes 7.8.1 Syndrome of Inappropriate Antidiuresis (SIAD) 7.8.2 Acromegaly 7.8.3 Cushing Syndrome 7.8.4 Hypercalcemia (PTHrP and MEN1) 7.9 Conclusions References 8: New Surgical Strategies 8.1 Introduction 8.2 Management of Small and Incidentally Discovered Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) 8.2.1 Pancreatic NETs 8.2.2 Gastric NETs 8.2.3 Duodenal NETs 8.2.4 Small Bowel NETs 8.2.5 Colorectal NETs 8.3 Surgical Management of Localized Gastroenteropancreatic (GEP)-NETs 8.3.1 Localized Pancreatic (Pan) NETs 8.3.1.1 Formal Resections and Lymphadenectomy 8.3.1.2 Parenchyma-Sparing Resections 8.3.2 Localized Gastric (G)-NETs 8.3.3 Localized Duodenal (D)-NETs 8.3.3.1 Localized Gastrinomas 8.3.4 Localized Small Bowel (SB)-NETs 8.3.5 Localized Colonic (C)-NETs 8.3.6 Localized Rectal (R)-NETs 8.3.7 Role of Minimally Invasive Surgery 8.3.7.1 Minimally Invasive Surgery for PanNETs 8.3.7.2 Minimally Invasive Surgery for G-NETs 8.3.7.3 Minimally Invasive Surgery for SB-NETs 8.3.7.4 Minimally Invasive Surgery for R-NETs 8.4 Surgery for G3 GEP-NENs 8.5 Surgery for Metastatic GEP-NETs 8.5.1 Surgery with Curative Intent 8.5.2 Palliative Resection of the Primary Tumor 8.5.3 Hepatic Cytoreduction 8.5.4 Liver Transplantation 8.6 Conclusions References 9: New Approaches in Medical Therapies 9.1 Introduction 9.2 Pasireotide 9.3 New Tyrosine Kinase Inhibitors 9.4 Immune Checkpoint Inhibitors 9.5 Cyclin-Dependent 4/6 Inhibitors 9.6 Epigenetic Drugs References 10: Locoregional Therapies of NEN 10.1 Introduction 10.2 Intra-Arterial Therapies 10.2.1 Embolization/Chemoembolization 10.2.2 Radioembolization 10.3 Percutaneous Liver Ablation 10.3.1 Radiofrequency Ablation 10.3.2 Microwave Ablation References 11: Radioreceptor Therapy 11.1 Introduction 11.2 Radiopharmaceuticals 11.3 Clinical Consideration 11.4 PRRT Administration 11.4.1 Side Effects of PRRT 11.4.2 Efficacy of PRRT in GEP-NETs 11.4.2.1 90Y-Labeled Somatostatin Analogues 11.4.2.2 177Lu-Labeled Somatostatin Analogues 11.4.2.3 Combination of 90Y/177Lu-Labeled Somatostatin Analogues 11.4.3 PRRT in Non-GEP-NETs 11.5 Combined Strategies in PRRT 11.6 New Developments in PRRT 11.7 Conclusion References Part IV: Treatment NETs from Different Organs 12: NETs of the Lung 12.1 Introduction and Epidemiology 12.2 Etiology and Classification 12.3 Histopathological Features and WHO Classification 12.4 Diagnostic Workup 12.4.1 Clinical Presentation 12.4.2 Imaging 12.5 Surgery 12.6 Endobronchial Resection 12.7 Somatostatin Analogues 12.8 Peptide Receptor Radiotherapy 12.9 Chemotherapy 12.10 Targeted Therapy 12.10.1 mTOR (Mammalian Target of Rapamycin) Inhibitors 12.10.2 Antiangiogenic Agents 12.11 Immunotherapy 12.12 Summary and Conclusions References 13: Gastric Neuroendocrine Tumors 13.1 Introduction 13.2 Clinical Presentation and Prognosis 13.2.1 Type I Gastric Neuroendocrine Tumors 13.2.2 Type II Gastric Neuroendocrine Tumors 13.2.3 Type III Gastric Neuroendocrine Tumors 13.3 Diagnosis and Tumor Staging 13.4 Treatment and Follow-Up 13.4.1 Localized Disease 13.4.1.1 Type I Gastric Neuroendocrine Tumors 13.4.1.2 Type II Gastric Neuroendocrine Tumors 13.4.1.3 Type III Gastric Neuroendocrine Tumors 13.4.2 Advanced Disease 13.5 Conclusions References 14: Treatment of Pancreatic Neuroendocrine Tumors 14.1 Introduction 14.2 Somatostatin Analogs 14.3 Peptide Receptor Radionuclide Therapy 14.3.1 Everolimus 14.4 Sunitinib 14.5 Locoregional Treatments for Liver Metastases 14.6 Chemotherapy 14.7 Conclusions References 15: Treatment of Intestinal NETs (Including Appendix) 15.1 Introduction 15.2 Medical Treatment for Advanced Disease 15.2.1 Somatostatin Analogs 15.2.2 Peptide Receptor Radionuclide Therapy 15.2.3 Everolimus 15.2.4 Chemotherapy 15.3 Liver-Directed Treatments for Hepatic Disease 15.4 Appendiceal Neuroendocrine Tumors 15.5 Conclusions References 16: Treatment of NETs from Rare Origin 16.1 Introduction 16.2 Oesophageal Neuroendocrine Tumours 16.2.1 Clinical Manifestation and Diagnosis 16.2.2 Treatment 16.2.2.1 Surgery 16.2.2.2 Chemotherapy (CT) 16.2.2.3 Radiotherapy (RT) 16.2.2.4 Peptide Receptor Radionuclide Therapy (PRRT) 16.2.2.5 Multidisciplinary Modalities 16.3 Thymic Neuroendocrine Tumours 16.3.1 Clinical Manifestation and Diagnosis 16.3.2 Treatment 16.3.2.1 Locally Resectable (or Borderline Resectable) Tumours 16.3.2.2 Unresectable, Recurrent and Metastatic Disease 16.4 Renal Neuroendocrine Tumours 16.4.1 Clinical Manifestation and Diagnosis 16.4.2 Treatment 16.4.2.1 Localized Disease 16.4.2.2 Advanced Disease 16.5 Gynaecologic Neuroendocrine Tumours 16.5.1 Cervical Neuroendocrine Tumours 16.5.2 Ovarian Neuroendocrine Tumours 16.5.3 Endometrial Neuroendocrine Tumours (eNETs) 16.5.4 Vaginal Neuroendocrine Tumours 16.6 Breast Neuroendocrine Tumours 16.6.1 Clinical Manifestation and Diagnosis 16.6.2 Treatment References Part V: NENs with Peculiar Biology and Features 17: Neuroendocrine Neoplasms with Peculiar Biology and Features: MEN1, MEN2A, MEN2B, MEN4, VHL, NF1 17.1 Introduction 17.2 MEN1 17.2.1 Overview 17.2.2 MEN1-Related NEN: Diagnostic and Therapeutic Update 17.3 MEN2 17.3.1 Overview 17.3.2 MEN2-Related NEN: Diagnostic and Therapeutic Update 17.3.2.1 MTC 17.3.2.2 Pheochromocytomas and Paragangliomas 17.4 MEN4 17.4.1 Overview 17.4.2 MEN4-Related NEN: Diagnostic and Therapeutic Update 17.5 Von Hippel–Lindau 17.5.1 Overview 17.5.2 VHL-Related NEN: Diagnostic and Therapeutic Update 17.5.2.1 Pancreatic NEN 17.5.2.2 Pheochromocytomas and Paragangliomas 17.6 Neurofibromatosis Type 1 17.6.1 Overview 17.6.2 NF1-Related NEN: Diagnostic and Therapeutic Update 17.6.2.1 Gastroenteropancreatic NEN 17.6.2.2 Pheochromocytomas and Paragangliomas References 18: Mixed Neuroendocrine and Non-neuroendocrine Neoplasms (Mi NEN) 18.1 Introduction and Terminology 18.2 Epidemiology 18.3 Pathogenesis 18.4 Diagnosis 18.4.1 The Exception that Proves the Rule 18.4.2 Mutational Landscape 18.4.3 Morphologic and Functional Imaging 18.4.4 Therapeutic Management 18.4.5 Prognosis 18.4.6 Conclusion References 19: Merkel Cell Carcinoma 19.1 Introduction 19.2 Epidemiology 19.3 Pathogenesis 19.3.1 Virus-Positive MCC 19.3.2 Virus-Negative MCC 19.3.3 Mutational Landscape of Virus-Positive (VP) and Virus-Negative (VN) MCCs 19.4 Risk Factors 19.5 Histology and Immunohistochemistry 19.6 Pathologic Report 19.6.1 Tumor Location 19.6.2 Margins 19.6.3 Lymphovascular Invasion 19.6.4 Tumor Thickness 19.6.5 Mitotic Index 19.6.6 Tumor-Infiltrating Lymphocytes 19.6.7 Tumor Growth Pattern 19.6.8 Second Malignancies 19.6.9 Nodal Evaluation 19.7 Staging System 19.7.1 T Category 19.7.2 N Category 19.7.3 M Category 19.7.4 Stage 19.7.5 Prognosis 19.8 Clinical Features 19.9 Staging Assessment 19.10 Management of Local/Locoregional Disease 19.10.1 Management of Primary Tumor 19.10.2 Management of Regional Lymph Nodes 19.10.3 Radiotherapy 19.10.4 Chemotherapy 19.11 Recurrent and Metastatic Disease 19.11.1 Systemic Treatment: From Chemotherapy to Immunotherapy 19.11.2 Target Agents References 20: Therapy in Poorly Differentiated Neuroendocrine Neoplasms (NEN G3) 20.1 Introduction and Histopathological Classification and Characteristics 20.2 Pulmonary Neuroendocrine Poorly Differentiated Neoplasms (LUNG NEN) 20.2.1 Histopathological Classification and Characteristics 20.2.2 Poorly Differentiated Lung Neuroendocrine Carcinomas NEC (SCLC and LCNEC) Treatment 20.2.2.1 Limited Stage Disease Treatment Radiochemotherapy Prophylactic Cranial Irradiation (PCI) 20.2.2.2 Advanced Stage Disease Treatment First-Line Chemotherapy Second-Line Chemotherapy Immunotherapy 20.3 Extrapulmonary G3 Neuroendocrine Neoplasms 20.3.1 Treatment of Extrapulmonary Neuroendocrine Carcinomas 20.3.1.1 First-Line Chemotherapy 20.3.1.2 Second-Line Chemotherapy 20.4 Treatment of Extrapulmonary G3 Neuroendocrine Tumor (NET) 20.4.1 Chemotherapy 20.4.1.1 Temozolomide 20.4.1.2 Platinum-Based Chemotherapy 20.4.2 Biological Treatment 20.5 Immunotherapy in GEP G3 NEN 20.6 Locoregional Therapy 20.7 Peptide Receptor Radionuclide Therapy (PRRT) References Part VI: Conclusions 21: Conclusions: NEN Management Today and Looking at the Future 21.1 Dedication