Work

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

Year: 2023

Type: article

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: 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 carbohydrates). Serum gastrin levels are measured at 15 min and 0 min before and every 15 min until 90 min after ingestion. Ectopic ACTH syndrome (1) Twenty-four-hour urine-free cortisol (UFC): Retaining of 24-h urine for cortisol level testing. A minimum of two tests should be performed. It is significantly elevated in patients with ectopic ACTH syndrome. (2) The circadian rhythm of serum cortisol: Cortisol levels should be measured at 8:00, 16:00, and 0:00. If the serum cortisol is >50 nmol/L (1.8 μg/dL) at 0:00 or >207 nmol/L (7.5 μg/dL) in the awake state, Cushing's syndrome is possibly indicated. (3) The 1 mg-overnight dexamethasone suppression test: The normal cut-off serum cortisol level after dosing is <50 nmol/L (1.8 μg/dL). However, serum cortisol levels cannot be suppressed in patients with ectopic ACTH syndrome. (4) Classical low-dose dexamethasone suppression test: In normal individuals, the 24-h UFC is <27 nmol, and serum cortisol is <50 nmol/L (1.8 μg/dL) on day 2 after oral dexamethasone. However, serum cortisol levels cannot be suppressed in patients with ectopic ACTH syndrome. (5) Plasma ACTH: A plasma ACTH level >500 pg/mL (110 pmol/L) is often indicative of ectopic ACTH syndrome. (6) Classical high-dose dexamethasone suppression test: If 24-h UFC or blood cortisol is suppressed by over 50% of the control value, Cushing's disease is suggested; otherwise, ectopic ACTH syndrome is indicated. (7) Bilateral inferior petrosal sinus sampling (IPSS) + desmopressin (DDAVP) stimulation test: The ACTH ratio of the inferior petrosal sinus to peripheral plasma ≥2 and/or ≥3 after DDAVP stimulation suggests Cushing's disease, ectopic ACTH syndrome is VIPoma fasting serum VIP from 0 pg/mL to with a of A fasting serum VIP level >200 ng/L is critical for diagnosing Serum VIP levels are significantly elevated in patients with with a value of involves the into the and to VIP and Somatostatin and are rare functioning tumors The corresponding hormones should be according to the clinical symptoms of the studies imaging and imaging are common imaging used for is a specific imaging used for pNENs. The of tumor is to the of on the of Owing to the in and the and of for primary and has in primary localization, clinical staging, treatment efficacy and of and However, for G3 NETs and NECs, the of 40–60% owing to the in diagnosis The imaging presentation of pNENs should be from that of tumors of the pancreas, pancreatic neoplasms and pancreatic [Table The clinical manifestations of functioning and non-functioning tumors should be from by other Table 2 - diagnosis and diagnosis of pNENs. pNEN Pancreatic in of blood of the Pancreatic among Pancreatic Pancreatic in of of blood has a low of can have Pancreatic in of type has a low pancreatic type has a high Pancreatic Pancreatic + lack of blood among and neoplasms; pNENs: Pancreatic neuroendocrine neoplasms; tumor. of The of tumors pNENs into NECs, and neoplasms are tumors with neuroendocrine and neuroendocrine as using to the and can be into and G3 The prognosis of G3 is than that of or than that of in the and that they to tumor pNENs are and mostly or The tumors have a and can be pNENs have a of or tumor cells with or The tumor cells or with in some pNENs are for and in The of hormones and may be using However, the diagnosis of functioning tumors should be on specific clinical and hormone as non-functioning tumors and The of is for the and pNENs Tumor involves the and according to the If are used and are the higher should be used for the The is by tumor cells in with the is and at least cells should be Standardized of and should include the tumor and tumor site, and of metastases, of or and Furthermore, the should assess the tumor and tumor differentiation, and assessments can be or are performed. the tumor is functioning is a clinical and usually in the [Table Table 3 - Standardized of pNENs. or of Tumor at least the and and of tumor and and Neuroendocrine CgA and related changes Diagnosis to the + + secondary diagnosis for Neuroendocrine tumor; Neuroendocrine pNENs: Pancreatic neuroendocrine staging, the on is 3 and The corresponding for pancreatic are for pNENs are highly heterogeneous tumors and them is A evaluation of the functional tumor site, differentiation, tumor burden, and disease should be performed to patient treatment is to a control tumor hormone symptoms, and improve treatment of treatment is the primary treatment and for The of is to should the tumor of the and the and of when the is for patients with functioning particularly those with symptoms. or non-functioning is the tumor is otherwise, is In patients with should be performed those performed for pancreatic evaluation evaluation of pNENs should include the (1) of the and patients with should be performed to the and valve (2) Tumor Specific biochemical indicators and corresponding such as plasma 24-h and plasma should be can be consulted for tumor and and functional assessments (3) Tumor imaging such as and are for tumor staging, and can be performed for of primary and/or (4) The of pNENs can be using or pNENs: The of and common and and should be If the or is the should be without for functioning pNENs or the the tumor and the pancreatic should be pNENs: The tumor may the pancreatic or with or the and whereas and is the tumor may the with the or thrombosis, and is pNENs: The tumor may the or or the is or and are owing to of the and of and the should be as should the site, and of (5) Serum Baseline levels of CA125, and other serum should be to and (6) of hereditary pNENs: and are primarily for functioning pNENs: The symptoms and syndromes by hormone should be to patient patients with insulinomas, of blood glucose levels is can be used to improve hypoglycemic symptoms, and can be used to insulin or are for gastrinomas to control diarrhea, peptic and other symptoms. have been to control and and glucagonomas, can be used to thrombosis, and can be used to migratory should be used to for patients with syndrome. pNENs should be performed in patients with pNENs to improve The primarily on the of the or tumor and the of Functioning pNENs: with sporadic functioning pNENs should more to symptoms, and improve (1) have a low and tumor is should be for peripheral however, they are with pancreatic is for tumors of the pancreatic whereas or is for tumors of the and is (2) functioning pNENs often have a higher such as gastrinomas, glucagonomas, and and regional are is with the of non-functioning pNENs. and can be for tumors (3) is for functioning pNENs for evaluation of the of the and corresponding are Gastrinoma is the most common functioning however, consensus has been on the and of patients are with using is for tumors measuring owing to the significantly increased risk of Similarly, is for insulinoma and Non-functioning pNENs: with non-functioning pNENs should other or high risk is (1) non-functioning in the absence of family or metastasis, the tumor and other is and is treatment should be more patients with significant as a increase during of regional or local pancreatic or jaundice, should be performed. (2) Non-functioning should be for and of with regional is (3) The on the of the the site, and of and are for non-functioning non-functioning measuring should be during the low risk of Furthermore, for tumors in the and to the pancreatic or tumors in the pancreas, the should be on a and is usually Standard should be performed for non-functioning with can be for pancreatic whereas with and is for pancreatic and treatment for patients with non-functioning is to that for those with sporadic a is in patients with The value of in are for pNENs: or has a incidence of critical and a with to can be in medical and pNENs pNENs are (1) of the pancreatic tumors of the pancreatic or the tumor the and (2) Tumor in the and and and are treatment is in patients with or pNENs the the and can be the treatment a (1) is for patients with functioning pNENs of the tumor cannot be is usually to symptoms and the of related (2) non-functioning in the of the primary and or and can be (3) non-functioning the in value for patients likely to as tumor can patient symptoms and may improve (4) is for patients with G3 and whereas may be increase the and improve patient should be performed in patients with or in have pNENs treatment for pNENs should be on the and of the and tumor and the and of Although the value for patients likely to for of the tumor burden, including primary and may relief and improve primary tumor can the of patients with pNENs. functioning pNENs: patients with is to symptoms, the of control tumor and including and and are non-functioning with should be according to the type of metastasis, and should be (1) patients with primary tumors and type metastases, all primary and lesions should be significantly in patients with primary tumors and type for are in patients may (2) patients with type metastases, or is of the primary and lesions could be and treatment such as should be (3) patients with type metastases, of the is whereas of the primary tumors may improve primary is accompanied by metastases, the of the is (4) Although the is most patients with pNEN develop is as a In of may be the are with absence of disease, history of of the primary in of the for those with hormonal and disease for at least 6 before G3 non-functioning and is for patient has been with including and may be to or critical such as and and for patients have is for patients to to the risk of symptoms and The of for patients with pNEN is to control symptoms and syndromes of functioning tumors and tumor and treatment control of functioning pNENs on the specific hormones by the and the treatment should be on the specific tumor and symptoms. In to medical or that secretory tumors are for [Table Table - control of functioning pNENs. or syndrome Insulinoma and oral or intravenous of glucose Gastrinoma are used they cannot be they can gastrin and gastric acid of should be of gastric acid may after in some patients with Carcinoid syndrome such as or patients with and can be increased as can be in cases of increased symptoms. If can be a multidisciplinary should be to the treatment Glucagonoma for or diabetes mellitus, Ectopic ACTH syndrome for ACTH Somatostatinoma VIPoma is a specific of The is in 3 or divided depending on the of is a at a of depending on the of for is is a of is particularly in patients cannot oral to or cortisol by effects on the and in the rapidly the whereas may or ACTH such as and can control by ACTH such as and may have a to efficacy in a patient effect on ACTH is usually and ACTH: Adrenocorticotropic hormone; pNENs: Pancreatic neuroendocrine neoplasms; Somatostatin VIPoma: Vasoactive intestinal peptide tumor. and effects is to the treatment for patients with The and of patients should be and the should be can be to tumors or G3 with rapid tumor to tumor and increase the and patient A multidisciplinary is required to develop a treatment include and with and clinical and response in in patients with is studies have that and in some patients with risk including the of symptoms jaundice, pain, and and and higher tumor studies or in pNENs are Chinese studies have that could tumor and improve in patients with patients with of with + + are However, clinical studies are required to treatment treatment treatment The of for patients with or pNENs include clinical symptoms associated with hormone from functioning tumors and tumor growth [Table and A multidisciplinary is when the treatment for a of the of the treatment symptoms, disease tumor burden, tumor differentiation, levels of biomarkers, and imaging functional Table - treatment for pNENs. Diagnosis or patients with tumor low tumor burden, or of + patients with with and/or low tumor and G3 in + + + + + patients with or patients with or patients with or the of or + + + patients with or The is in clinical trials is highly In the a of in patients with with in the A in patients with the was with with The response was in The of in patients when with the was and The of was In the from to with for with in and The and with with high-dose in patients on as as significantly symptoms and of to the from the is for G3 patients with however, may be pNENs: Pancreatic neuroendocrine neoplasms; Somatostatin Somatostatin Somatostatin tumor and of In and used in including and are [Table Table 6 - and treatment for pNENs. Diagnosis or + + + + + + + + patients with G3 patients with tumor or + patients with tumor or + + + patients with tumor patients with tumor + + + + + patients with or patients with tumor + + are for patients have in the However, the disease on treatment with should be for non-functioning for functioning or every is 3 day can be the studies have of in patients with of the functional or tumor A that in a of and a of in patients with NETs previously with is the disease on a studies reported of with patients with A clinical the efficacy of the in patients with some of and the disease control in patients was A the efficacy of a in patients with of was in patients with and response the of response was The is a in patients with rare 3 and 1 every 3 for by 3 every 2 until disease or in patients response the clinical is the efficacy of in patients without or response pNENs: Pancreatic neuroendocrine neoplasms; von Somatostatin Somatostatin tumor Chinese treatment pNENs have been in in of as or according to etiology and the is more in than in those It usually with and deficiency in and or to on for treating pNENs are In clinical are primarily on deficiency and the and and specific treatment on the the differentiation of the symptoms and signs in that Chinese with could the to treatment in patients with neuroendocrine neoplasms including with in and the the and in the patients with among pNENs and patients the and the that disease and disease with of and at 6 and The was treatment The of for pNENs to that for pancreatic and is all tumor and all may be treatment for patients are for Similarly, is in and as for patients with patients with local or local control and the of for pNENs however, as pNENs have and than pancreatic is in such treatment The is the most common of of with a of of pNENs usually as on and over of the blood from the that is the treatment for patients with include and The significant in the efficacy of patients with and a high tumor treatment is to effects and patients have or should be to the risk of such as and used for pNEN primarily include and can efficacy to that of for primary with a should be early in patients other to a can be performed or during or Similarly, treatment could be treatment for to other is of Diagnosis and patients with the for the diagnosis and treatment is in the treatment should be and a multidisciplinary of including medical and of diagnosis and of pNENs. pNENs: Pancreatic neuroendocrine neoplasms; Somatostatin Somatostatin a significant in the of and the can depending on patient such as tumor of metastasis, and the of the treating for the of pNENs. pNENs: Pancreatic neuroendocrine neoplasms; pancreatic neuroendocrine Non-functioning pancreatic neuroendocrine The prognosis of patients with pNENs is closely related to tumor and is for all The should tumor and treatment whether was patients the should be and patients should for symptoms The should include serum biochemical such as CgA and imaging such as and and imaging such as and patients with functioning corresponding biochemical indicators as blood and hormone levels as insulin and should be the of into disease has been However, including and have the diagnosis and treatment of pNENs and are for in is a and that using of the studies have clinical value in diagnosing and predicting tumor and recurrence, with significantly higher than biomarkers, such as CgA and imaging with and imaging such as have been into clinical imaging with in a and some studies have as to imaging have emerged in the for studies found a higher tumor and and tumor of the and than those of the used or such as G3 NETs and NECs, should be on to pNENs however, a few have been with in has and are to develop multiple with or A clinical of as a treatment for is in studies are specific or other such as in patients with pNENs. This consensus the and of all of the Pancreatic Tumor Group of the Oncology Society of the Chinese Medical all Consensus experts for in and Similarly, are to the experts for and in the are family and This was by from the for the and of diagnosis and treatment in Clinical and and Clinical of of

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000002848