Incidence and epidemiology
Methodology
Diagnosis, staging, and risk assessment
Histological diagnosis
2019 WHO classification of gastroenteropancreatic neuroendocrine neoplasms | 2015 WHO classification of pulmonary neuroendocrine neoplasms | |||||
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Terminology | Differentiation | Grade | Mitotic count (2 mm2)a | Ki-67 index (%)a | Terminology | Criteria |
Neuroendocrine tumor G1 | Well differentiated | G1 | < 2 | < 3 | Typical carcinoid | Carcinoid morphology < 2 mitoses/2 mm2 No necrosis |
Neuroendocrine tumor G2 | Well differentiated | G2 | 2–20 | 3–20 | Atypical carcinoid | Carcinoid morphology 2–10 mitoses/2 mm2 Necrosis (often punctuate) |
Neuroendocrine tumor G3 | Well differentiated | G3 | > 20 | > 20 | Large cell neuroendocrine carcinoma | ≥ 11 mitoses/2 mm2 (median 70/2 mm2) Necrosis (often large zones) Cytologic features of NSCLC |
Neuroendocrine carcinoma Small cell type Large cell type | Poorly differentiated | G3 | > 20 | > 20 | Small cell neuroendocrine carcinoma | ≥ 11 mitoses/2 mm2 (median 80/2 mm2) Necrosis (often large zones) Cytologic features of SCLC |
Mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN)b | Well or poorly differentiated | Variable |
Staging and risk assessment
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Biochemical markers: Chromogranin A (III, B), 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) in metastatic SI-NETs regardless of symptoms and lung tumors with carcinoid syndrome (III, A), specific hormones in pancreatic or lung NENs presenting with suspected hormonal syndromes (e.g., insulin for insulinomas, glucagon for glucagonomas, cortisol/ACTH for Cushing syndrome) (III, A) [13].
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Anatomic imaging: Computed tomography (CT) constitutes the basic radiological study for the assessment of location and extent of disease. NETs are generally hypervascular and best visualized in the late arterial phase. Triphasic helical CT of the abdomen and pelvis should therefore be used for the optimal evaluation of liver metastases. Chest CT is also recommended to study lung metastases (III, A). Magnetic resonance imaging (MRI), particularly contrast-enhanced MRI utilizing hepatocellular phase-contrast agents, should be preferred compared with CT for the detection of small liver metastases, pancreas, and bone lesions as a result of its higher sensitivity (III, A) [14].
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Functional imaging: Because most NETs overexpress high-affinity somatostatin receptors (SSTR), SSTR-based imaging should be part of the initial staging (II, A). Gallium-68 (68Ga)-DOTATATE PET/CT has become the preferred modality for SSTR imaging as a result of its higher sensitivity for baseline whole-body staging, detecting of small lymph-node or bone metastases, and identification of the primary site in cases of occult origin (II, A) [14, 15]. SSTR scintigraphy can be used if 68Ga PET/CT is not available, although is considerably less sensitive (III, B). 18F-fluorodeoxyglucose PET/CT (FDG-PET/CT) may be considered to refine prognosis in high G2 and G3 NENs, which generally have less SSTR expression and higher glucose metabolisms than low-grade NETs, negative SSTR imaging or rapidly growing disease (III, B) [14].
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Additional diagnostic recommendations vary by disease site and stage and include endoscopic procedures, brain CT/MRI in high-risk lung or NT-pro-BNP and echocardiogram for the evaluation of carcinoid heart disease in SI, lung, and thymic with carcinoid syndrome tumors (III, A) [13].
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Genetic risk evaluation and testing for hereditary endocrine neoplasia syndromes, such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, tuberous sclerosing complex, or Von Hippel Lindau syndrome, must be performed when there is a well-founded suspicion (III, A) [13].
G1–G3 neuroendocrine tumors (NETs)
Management of local and locoregional disease
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Locoregional approach to a primary NET should be systematically discussed in the multidisciplinary team [III, A].
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Pancreatic and gastric G1 non-functioning NETs with less than 10 mm can be followed using a “watch and wait” strategy [III, A].
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Surgical resection should be discussed with the patients for gastric and pancreatic tumors greater than 20 mm [III, A].
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NETs with a periampullary location should be faced by radical surgery plus lymphadenectomy if size is greater than 15 mm [III, B].
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aNETs that exceed 20 mm, present with mesoappendix infiltration, lymphovascular invasion, or high tumor grade should be considered for additional colectomy with lymphadenectomy [III, B].
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Lung carcinoids over 10 mm, functioning ones or those that experience progression, should be considered for sublobar surgical approaches including wedge resection [III, A].