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

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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: Zollinger–Ellison syndrome; CNS: central nervous system; 5-HT: 5-hydroxyptamine. Non-functioning tumors represent 66% of pNENs. The incidence could be higher than that previously reported owing to the absence of a typical clinical presentation in the early stage.[3,12] The clinical manifestations of non-functioning tumors are non-specific and are primarily related to the local compression effects of primary lesions and metastases, including regional pain, jaundice, abnormal bowel movements, fever, and gastrointestinal (GI) bleeding. Laboratory tests Peripheral blood biomarker test Serum chromogranin A (CgA), the most critical universal biomarker for neuroendocrine tumors (NETs), is used to assist in diagnosis and to assess the response and prognosis.[13,14] The efficacy of CgA in diagnosing and treating pNENs may be influenced by the tumor type, primary site, tumor differentiation, tumor burden, and secretory functionality. Owing to the absence of unified clinical standards for CgA testing in China, more caution is required in applying and interpreting CgA testing.[14] Neuron-specific enolase (NSE) levels are significantly elevated in some patients with high-grade NETs or neuroendocrine carcinomas (NECs). Baseline NSE levels and post-treatment changes are strongly associated with prognosis.[15,16] Similarly, serum procalcitonin levels, mostly elevated in G3 NETs and NECs, can be used for tumor monitoring.[17] Furthermore, other tumor serum biomarkers, including carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 199 and CA125, may be valuable for diagnosing and predicting recurrence, metastasis, and prognosis of pNENs; however, they lack specificity.[18] Laboratory tests for functioning pNENs Specific biochemical indicators and corresponding hormone levels should be monitored closely according to the tumor type, and endocrinologists should be consulted for qualitative, localization, and functional assessments of the tumor. Insulinoma The cut-off value for hypoglycemia was 55 mg/dL, or 3 mmol/L. It is characterized by plasma insulin ≥3.0 μIU/mL (18 pmol/L), plasma C-peptide ≥0.6 ng/mL (0.2 nmol/L), plasma proinsulin ≥5.0 pmol/L (without sulfonylurea), and insulin release index: plasma insulin (μIU/mL)/plasma glucose (mg/dL) >0.4. The 48-h or 72-h fasting test was performed to establish a diagnosis of endogenous hyperinsulinemia in a few patients with asymptomatic hypoglycemia and those with high suspicion of insulinoma without hypoglycemic episodes.[19] Gastrinoma Serum gastrin >1000 ng/L and gastric acid pH <2. Stimulation tests, that is, secretin stimulation, calcium stimulation, and standard meal tests, are performed for patients with serum gastrin levels >200 ng/L and <1000 ng/L. Serum gastrin levels in patients with gastrinomas are characterized by fasting hypergastrinemia[20] (>150 pg/L), a rapid and significant increase in serum gastrin after intravenous secretion, and a significant increase in serum gastrin after calcium injection. (1) The secretin stimulation test is the most valuable for identifying gastrinomas. Pure porcine secretin (2 U/kg) is injected intravenously within 30 min, and the serum specimen is measured using a radioimmunoassay. In patients with gastrinoma, the serum gastrin concentration increases rapidly (within 2–10 min) by at least 200 pg/L after injection and gradually returns to the pre-injection level. (2) Calcium stimulation test: This involves measuring radioimmuno-labeled gastrin in blood samples drawn 30 min before and every 30 min after calcium injection for a total of nine times. Eighty percent of patients with gastrinoma show increased gastrin release after calcium injection, and most of them show a significant increase in gastrin concentration (>400 pg/L). Gastrin concentration usually peaks shortly after injection. (3) Standard meal test: This test involves using one slice of bread, 200 mL of milk, one hard-boiled egg, and 50 g of cheese (containing 20 g fat, 30 g protein, and 25 g ca

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