Chinese Medical Association consensus for standardized diagnosis and treatment of pancreatic neuroendocrine neoplasms

Abstract

Pancreatic neuroendocrine neoplasms (pNENs) are rare and highly heterogeneous tumors originating from pluripotent stem cells with neuroendocrine differentiation in the pancreas, constituting approximately 3% of all pancreatic tumors.[1] The global incidence of pNENs has been increasing recently, and most cases are sporadic and more common in women.[1,2] pNENs are clinically divided into functioning and non-functioning tumors depending on whether the tumors are accompanied by a clinical syndrome related to specific hormone overproduction. Functioning tumors are usually diagnosed during the early evaluation of hormonal syndromes, whereas most non-functioning pNENs are accidentally found during imaging studies and endoscopies for other complaints, such as the mass effect of local growth or secondary symptoms owing to metastasis.[2,3] The etiology of pNENs is partially known and may be related to genetic mutations, family history of cancer, cigarette smoking, alcohol consumption, and other risk factors.[4,5] Although most pNENs are sporadic and likely carry somatic mutations in death domain-associated protein 6 (DAXX) and ATP-dependent helicase (ATRX),[6] they may develop in patients with hereditary endocrinopathies, including multiple endocrine neoplasia type 1 (MEN1),[7] von Hippel–Lindau (VHL) syndrome,[8] neurofibromatosis type 1 (NF1),[9] and Tuberous Sclerosis Complex (TSC).[10] Evidence for diagnosing, staging, and treating pNENs has emerged over the past few years, particularly in original trials among the Chinese population. Based on this, the Pancreatic Tumor Group of the Oncology Society of the Chinese Medical Association convened a writing committee of multidisciplinary experts to compile Chinese Medical Association Consensus for the Standardized Diagnosis and Management of Pancreatic Neuroendocrine Neoplasms (2022). This consensus will positively influence standardizing pNEN diagnosis and treatment in China, improve patient prognosis, and optimize medical resources. Diagnosis Clinical manifestations Functioning tumors account for approximately 34% of pNENs and include insulinomas, glucagonomas, gastrinomas, vasoactive intestinal peptide tumors (VIPomas), somatostatinomas, and adrenocorticotropic hormone (ACTH)-producing tumors.[3,11] Clinical manifestations of specific syndromes arising primarily from secreted hormones have been presented[11] [Table 1]. Table 1 - Clinical manifestations of functioning pNENs. Tumor type Percentage Primarily secreted hormones Main symptoms Insulinoma 40–60% Insulin Whipple's triad: symptoms and signs of hypoglycemia (tremors, palpitations, hunger, etc.), especially CNS symptoms (cognitive impairment, seizures, coma, etc.); low blood plasma glucose level (<2.8 mmol/L); relief of symptoms when glucose level is increased. Gastrinoma 20–50% Gastrin ZES: refractory peptic ulcer, gastroesophageal reflux symptoms, abdominal pain, diarrhea, etc. Glucagonoma Rare Glucagon Glucagonoma syndrome: NME, diabetes mellitus, venous thrombosis, intermittent diarrhea, weight loss, depression, and other psychiatric symptoms. Somatostatinoma Rare Somatostatin Somatostatinoma or "Inhibitory" syndrome: a triad of mild diabetes mellitus, cholelithiasis, and diarrhea/steatorrhea; other symptoms such as gastric acid deficiency and weight loss. ACTH-producing tumor Rare ACTH Cushing syndrome: obesity, acne, rounded face, hirsutism, hypertension, fatigue, depression, dorsocervical fat pad, impaired glucose tolerance, proximal muscle weakness, menstrual irregularities, infertility, etc. VIPoma Rare VIP Verner–Morrison syndrome (pancreatic cholera syndrome): watery diarrhea, hypokalemia, dehydration, gastric acid deficiency, etc. Carcinoid Rare 5-HT (serotonin), tachykinin Carcinoid syndrome: flushing, diarrhea, bronchospasm, heart valve disease, etc. ACTH: Adrenocorticotropic hormone; NME: Necrolytic migratory erythema; pNENs: Pancreatic neuroendocrine neoplasms; VIPoma: Vasoactive intestinal peptide tumor; ZES: Zo