Neuroendocrine Tumours
NETs and NEC — gastroenteropancreatic and lung
DefinitionClick to collapse
Gastric neuroendocrine tumors (gNETs) are well-differentiated neuroendocrine neoplasms arising from enterochromaffin-like (ECL) cells of the gastric mucosa. They are classified into distinct subtypes based on underlying etiology, histological features, and clinical behavior. Type 1 gNETs occur in the context of chronic atrophic gastritis (autoimmune or H. pylori-related) leading to hypergastrinemia and ECL-cell hyperplasia; these are typically multifocal, small (<1 cm), and have a low metastatic risk (<5%). Type 2 gNETs are associated with hypergastrinemia from gastrinomas (Zollinger-Ellison syndrome), often in patients with multiple endocrine neoplasia type 1 (MEN1), and are also multifocal but carry a higher metastatic potential. Type 3 gNETs are sporadic, unifocal, and arise in normal gastric mucosa with normal gastrin levels; these are more aggressive with a higher propensity for metastasis. A fourth category, often termed 'other' or PPI-induced gNETs, is linked to long-term proton pump inhibitor (PPI) use, which causes hypergastrinemia and ECL-cell hyperplasia; these tumors appear to have a much lower propensity to metastasize compared to sporadic type 3 tumors. Gastric NETs are part of the broader group of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and are typically slow-growing, but accurate subtyping is crucial for prognosis and management. The diagnosis requires endoscopic evaluation with biopsy and assessment of gastrin levels, and staging is based on tumor size, depth of invasion, and lymph node status. [References: NCCN Guidelines v1.2026, NET-1, Discussion MS-10, MS-11]
EpidemiologyClick to collapse
SubtypesClick to collapse
Clinical FeaturesClick to collapse
Typical Presentation
Neuroendocrine tumors (NETs) are a broad family of neoplasms arising from the diffuse endocrine system, most commonly originating in the gastrointestinal tract, lungs/bronchi, thymus, and pancreas [1,2]. Patients may present with symptoms of hormone hypersecretion (functional tumors) or with mass-effect symptoms (nonfunctional tumors). Approximately 8% to 28% of patients with GI NETs develop carcinoid syndrome [102,103], characterized by flushing, diarrhea, bronchoconstriction, and cardiac valvular fibrosis. Pancreatic NETs (PanNETs) include functioning tumors such as gastrinomas (peptic ulcers), insulinomas (fasting hypoglycemia), glucagonomas (necrolytic migratory erythema), and VIPomas (watery diarrhea, hypokalemia, achlorhydria). Nonfunctional PanNETs account for approximately 60% to 91% of cases [14,73]. Pheochromocytomas (PCCs) and paragangliomas (PGLs) present with hypertension, tachycardia, sweating, and paroxysmal headache. Adrenocortical carcinomas (ACCs) present with symptoms of hormone excess in approximately 60% of patients or with tumor-related symptoms such as abdominal pain and weight loss [21].
Symptoms
Flushing
Episodic cutaneous vasodilation, predominantly in the face and upper trunk, typically occurring in the context of carcinoid syndrome. Serotonin, histamine, tachykinins, and other vasoactive substances contribute to flushing. Etiology of flushing is less well understood than that of diarrhea [12,100].
Diarrhea
Carcinoid syndrome–associated diarrhea is caused by serotonin and other vasoactive peptides. Diarrhea is multifactorial in NET patients and may also be caused by direct side effects from somatostatin analogs (SSAs), pancreatic exocrine insufficiency resulting in steatorrhea, bile malabsorption from ileocecectomy or cholecystectomy, and short-gut syndrome [NE-K].
Peptic ulcer disease
Gastrinomas secrete gastrin, causing recurrent peptic ulcers, dyspepsia, and diarrhea. Approximately 70% of patients with MEN1 and gastrinoma have tumors in the duodenum [244]. Zollinger-Ellison syndrome results from gastrin hypersecretion.
Hypoglycemia
Insulinomas secrete insulin resulting in fasting or nocturnal hypoglycemia. Approximately 70% to 90% of sporadic insulinomas are benign and can be cured surgically. Evaluation with a 72-hour fast tests serum insulin, pro-insulin, and C-peptide during concurrent hypoglycemia [245].
Necrolytic migratory erythema
Characteristic dermatitis of glucagonomas, often accompanied by hyperglycemia or diabetes mellitus, weight loss, cachexia, and a hypercoagulable state (10%–33% risk of thromboembolic events) [270,271].
Watery diarrhea with hypokalemia and achlorhydria (WDHA syndrome)
VIPomas secrete vasoactive intestinal peptide causing severe secretory diarrhea with profound electrolyte depletion and dehydration. Also known as Verner-Morrison syndrome.
Cushing syndrome
Ectopic adrenocorticotropic hormone (ACTH) production by bronchial or thymic NETs can cause Cushing syndrome. Bronchial and thymic NETs have been associated with ectopic ACTH production [98,99]. Also may occur from adrenal adenoma, adrenal carcinoma, pituitary adenoma, or ectopic sources (lung or thymic NETs). Clinical features include central weight gain, striae, hypertension, hyperglycemia, depression, hirsutism, and muscle weakness [NE-A 2 of 4].
Acromegaly
GH-secreting pituitary adenomas in MEN1 syndrome, or rarely ectopic GH secretion by other NETs.
Hypertension (paroxysmal or sustained)
PCCs release catecholamines (epinephrine and norepinephrine) and their metabolites metanephrine and normetanephrine, resulting in hypertension, arrhythmia, and/or hyperglycemia. Symptoms include sweating, paroxysmal headache, pallor episodes, and syncope (very rare) [NE-A 2 of 4]. PGLs secrete catecholamines in about 40% of cases. Head and neck PGLs secrete catecholamines only about 5% of the time.
Virilization/Feminization
Androgen-secreting ACCs in females may induce hirsutism, virilization, deepening of the voice, and oligo/amenorrhea. In males, estrogen-secreting tumors may induce gynecomastia and testicular atrophy. Approximately 60% of ACC patients present with evidence of adrenal steroid hormone excess [21].
Abdominal pain / mass effect
Nonfunctioning tumors may present with symptoms related to local growth including abdominal pain, back pain, early satiety, and weight loss. Small bowel NETs often present with intermittent abdominal pain from episodic bowel obstruction or bowel ischemia related to the primary tumor and surrounding fibrosis.
Respiratory symptoms
Lung NETs may present with cough, hemoptysis, wheezing, recurrent pneumonia, or incidental pulmonary nodules. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) presents with chronic cough and dyspnea.
Hypercalcemia
Primary hyperparathyroidism associated with MEN1 or MEN2, characterized by elevated serum calcium. The most common manifestation of MEN1 is parathyroid adenoma/hyperplasia (present in >98% of patients) [10,494].
Visual field defects / headache
Pituitary adenomas in MEN1 may present with headaches, visual field deficits, galactorrhea (prolactinoma), or amenorrhea. About 30%–40% of MEN1 patients have functioning pituitary tumors [10,493].
Signs
Flushing
Episodic erythema of the face and upper trunk, a hallmark of carcinoid syndrome. May occur with diarrhea and bronchospasm.
Hepatomegaly
Palpable liver from metastatic disease, commonly seen in midgut NETs with hepatic metastases. The liver is the most common metastatic site for NETs.
Cardiac murmur (tricuspid regurgitation/pulmonary stenosis)
Carcinoid heart disease (CHD) causes valvular fibrosis, predominantly affecting the tricuspid and pulmonary valves. Approximately 50% to 66% of patients with carcinoid syndrome develop valvular cardiac complications [101]. Echocardiographic diagnosis should include morphologic evaluation of valves and assessment of right heart size and function [NE-B 2 of 5].
Peripheral edema / ascites
Signs of right-sided heart failure from carcinoid heart disease or from portal hypertension/hepatic insufficiency related to extensive liver metastases.
Central obesity, striae, hypertension
Clinical features of hypercortisolemia (Cushing syndrome), which may be caused by ACTH-secreting pituitary adenoma, adrenal cortical tumor, or ectopic ACTH from bronchial/thymic NETs. Also includes proximal muscle weakness, hyperglycemia, depression, and hirsutism [NE-A 2 of 4].
Hirsutism / virilization
Androgen-secreting adrenal cortical carcinoma causing hirsutism, virilization, deepening voice, and menstrual irregularities in females.
Gynecomastia
Estrogen-secreting adrenal cortical carcinoma or testicular atrophy.
Pallor, diaphoresis, tachycardia
During paroxysmal hypertensive episodes in pheochromocytoma, patients may exhibit pallor, profuse sweating, and tachycardia. Syncope is very rare [NE-A 2 of 4].
Abdominal mass
Large nonfunctioning PanNETs or ACC may be palpable on abdominal examination.
Mucosal neuromas / Marfanoid habitus
Clinical features of MEN2B, including mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies, Marfanoid body habitus, and poor dentition. Nearly all patients with MEN2B have Marfanoid habitus [232].
Cafe-au-lait spots / neurofibromas
Features of neurofibromatosis type 1, which is associated with an increased risk of PCC (~3%) and rare PanNETs.
Red FlagsClick to collapse
Carcinoid crisis: life-threatening massive release of vasoactive substances triggered by tumor manipulation or anesthesia, with severe hemodynamic instability (hypotension, tachycardia, arrhythmias), diarrhea, and bronchoconstriction; prophylactic octreotide is likely ineffective in preventing intraoperative carcinoid crisis [NE-K]; intraoperative octreotide should not delay vasopressor use and fluid administration
Paroxysmal hypertensive crisis with headache, diaphoresis, and tachycardia: suggests pheochromocytoma and requires evaluation with plasma free metanephrines before any surgical procedure or invasive intervention
Refractory peptic ulcer disease with diarrhea: suggests gastrinoma/Zollinger-Ellison syndrome and requires serum gastrin measurement; PPI use should ideally be paused to confirm diagnosis but continued if patient has overt symptoms or risk of complications
Hypoglycemia with neuroglycopenic symptoms: suggests insulinoma and requires 72-hour supervised fast with concurrent measurement of insulin, pro-insulin, and C-peptide; rule out other causes of hypoglycemia first
Severe secretory diarrhea with hypokalemia and achlorhydria: suggests VIPoma (Verner-Morrison syndrome)
Necrolytic migratory erythema with diabetes and weight loss: suggests glucagonoma; evaluate for hypercoagulable state (10%–33% risk) [270,271]
New-onset Cushing syndrome features: requires evaluation for ACTH-secreting pituitary adenoma, adrenal tumor, or ectopic ACTH source including bronchial/thymic NETs [NE-A 2 of 4]
Sustained or paroxysmal hypertension in a young patient (<45 years) or with family history of endocrine tumors: suggests hereditary PCC/PGL syndrome requiring genetic counseling and testing [19,448]
Adrenal mass >4 cm or with irregular margins, heterogeneity, or invasion: suspicion for adrenocortical carcinoma requiring staging workup with FDG-PET/CT, chest CT, and adrenal protocol CT or MRI [21]
Symptoms of carcinoid heart disease: dyspnea, fatigue, edema, or ascites in patients with known carcinoid syndrome; echocardiography required
Hereditary syndrome red flags: presence of 2+ MEN1-associated tumors (parathyroid hyperplasia, enteropancreatic NETs, pituitary tumors), MTC with or without PCC (MEN2), bilateral PCC, family history of endocrine tumors, or known pathogenic germline variant
Perioperative hemodynamic instability during surgery for suspected carcinoid syndrome: requires immediate treatment with vasopressors and fluid resuscitation; do not delay for octreotide administration
InvestigationsClick to collapse
Diagnostic
Plasma free or 24-hour urine fractionated metanephrines and catecholamines
Primary diagnostic test for pheochromocytoma and paraganglioma. Elevations 3 times above the upper limit of normal are diagnostic [NE-A 2 of 4]. For cervical PGL, measurement of serum/24-hour urine fractionated catecholamines (for dopamine) or methoxytyramine may be appropriate.
Serum gastrin level
Diagnostic for gastrinoma/Zollinger-Ellison syndrome. Must be measured fasting and ideally off PPI therapy for >1 week, though PPI should be continued in patients with overt clinical symptoms or complication risk [244, NE-A 3 of 4].
24-hour urine or plasma 5-HIAA
Evaluation of serotonin secretion for carcinoid syndrome diagnosis. Recommended in patients with symptoms consistent with carcinoid syndrome (flushing, diarrhea) [NE-A 1 of 4].
Fasting blood glucose, insulin, pro-insulin, C-peptide
Diagnostic workup for suspected insulinoma during concurrent hypoglycemia. Gold standard is 72-hour supervised fast [245].
Serum glucagon and blood glucose
Evaluation for suspected glucagonoma in patients with recent-onset diabetes, cachexia, and/or necrolytic erythematous skin rash.
Serum VIP, electrolytes
Evaluation for suspected VIPoma presenting with watery diarrhea.
Serum somatostatin
Evaluation for suspected somatostatinoma presenting with hyperglycemia, cholelithiasis, and diarrhea/steatorrhea.
Serum chromogranin A
Often elevated in patients with NETs (>60% of patients with functioning or nonfunctioning PanNETs) [238-240]. Elevated levels to twice the normal limit or higher are associated with shorter survival times (HR, 2.8; 95% CI, 1.9–4.0; P < .001) [241]. However, should not be relied upon in isolation due to false elevations from PPIs, renal or liver failure, hypertension, and chronic gastritis [115-117].
Plasma aldosterone and plasma renin activity
Evaluation for primary aldosteronism. Screening test for suspected adrenal cortical aldosterone-producing adenoma.
Overnight 1-mg dexamethasone suppression test / 2-3 midnight salivary cortisols / 24-hour urinary free cortisol
Screening for hypercortisolemia (± Cushing syndrome) in patients with symptoms suggesting cortisol excess [NE-A 2 of 4].
Plasma ACTH / AM cortisol
To determine if hypercortisolemia is ACTH-dependent (pituitary or ectopic source) or ACTH-independent (adrenal source) [NE-A 2 of 4]. ACTH <5 pg/mL suggests ACTH-independent disease.
Adrenal androgens (DHEA-S, androstenedione, testosterone, 17-hydroxyprogesterone)
Evaluation for sex steroid excess in suspected adrenocortical carcinoma. ACC can secrete multiple hormones [NE-A 2 of 4].
Pituitary hormones panel
Evaluation for pituitary adenomas in MEN1: serum IGF-1 (category 2B), serum prolactin, LH/FSH, gonadotrophin with end organ hormone, alpha subunits (mainly in non-secretory tumors), TSH and free T4, plasma ACTH/AM cortisol, total and free testosterone, estradiol [NE-A 2 of 4].
Calcitonin and CEA
Evaluation for medullary thyroid carcinoma in MEN2. Basal calcitonin and CEA levels guide extent of nodal dissection required.
Serum calcium and albumin
Annual screening for hyperparathyroidism in MEN1. If calcium rises, further workup needed.
Parathyroid hormone (PTH)
If calcium is elevated, PTH measurement confirms primary hyperparathyroidism.
Molecular profiling of tumor tissue (NGS panel)
Recommended for patients with locoregional unresectable/metastatic disease who are candidates for anticancer therapy to identify actionable alterations. Testing should specifically consider NTRK fusions, RET fusions, BRAF V600E mutations, MSI-H, dMMR, and TMB-H [PDNEC-1 footnote g]. For PDNEC, testing on tumor tissue is preferred; ctDNA testing can be considered if tumor tissue testing is not feasible.
Genetic counseling and germline genetic testing
Recommended for patients meeting criteria in Principles of Hereditary Cancer Risk Assessment (NE-F). Mandatory for ACC, PCC/PGL, MEN1/MEN2 features, multifocal PanNETs, gastrinomas, thymic NETs, and others [NE-F 1 of 6].
Staging
Multiphasic abdomen/pelvis CT or MRI with IV contrast
Primary cross-sectional imaging for evaluation of GI NETs, PanNETs, and adrenal tumors. Multiphase (arterial and portal venous phase) is important because NETs frequently enhance in the arterial phase [NE-B 1 of 5]. Consider same imaging modality for follow-up studies.
Chest CT ± contrast
Evaluation for lung metastases and primary thoracic NETs. For lung/thymic NETs, chest CT with contrast is recommended. Also part of surveillance for all NETs.
SSTR-PET/CT or SSTR-PET/MRI (68Ga-DOTATATE, 64Cu-DOTATATE, or 68Ga-DOTATOC)
Functional imaging to assess somatostatin receptor status and distant disease. SSTR-positive if uptake in measurable lesions is greater than liver. Essential for determining eligibility for PRRT with lutetium Lu 177 dotatate. Sensitivity and specificity for initial diagnosis of NETs: pooled 91% and 94% respectively [111]. Modified Krenning score (0–4) for qualitative assessment [NE-B 1 of 5]. Should be performed concurrently with diagnostic multiphase CT or MRI when possible.
FDG-PET/CT
Functional imaging for higher-grade or poorly differentiated tumors. May identify more aggressive disease. Combining FDG-PET and SSTR-PET gives more prognostic value than either alone [NE-B 1 of 5, references 1,2]. Consider in well-differentiated grade 3 NETs and when considering PRRT.
Endoscopic ultrasound (EUS) ± biopsy
For gastric, duodenal, and rectal NETs to determine depth of invasion and assess for lymphadenopathy. Also for pancreatic NETs to preoperatively assess and localize tumors.
EGD (esophagogastroduodenoscopy) with biopsies
Essential for evaluation of gastric NETs. Required to determine subtype (type 1, 2, 3, PPI-associated). High-definition white light endoscopy with video chromoendoscopy recommended. Biopsy protocol: minimum 2 biopsies from antrum (lesser and greater curvature), 1 from incisura, and 2 from gastric body [NET-1A footnote b, reference 10].
Colonoscopy
Evaluation for ileal and colon NETs, and to evaluate for synchronous lesions.
Rectal MRI or endorectal ultrasound
Staging for rectal NETs to assess depth of invasion and regional lymphadenopathy.
Brain MRI or CT with contrast
Evaluation for pituitary adenomas (MEN1) and brain metastases (poorly differentiated NECs). Generally not required for well-differentiated NETs [NE-B 1 of 5].
Bronchoscopy
Evaluation for endobronchial lesions in suspected lung NETs.
MIBG scan with SPECT/CT
For PCC/PGL: less sensitive than FDG-PET and 68Ga-DOTATATE for metastatic and multifocal PCC/PGL in patients with VHL and SDH syndromes [447]. MIBG scans should be obtained if considering treatment with I131-MIBG. SPECT/CT imaging of involved sites is recommended [PHEO-1 footnote j].
Selective arterial calcium stimulation test (Imamura-Doppman procedure)
For localization of insulinoma when imaging is negative or equivocal. Injection of calcium into selective pancreatic arteries with measurement of insulin levels in hepatic veins.
4D-CT (four-dimensional computed tomography) or parathyroid sestamibi with SPECT/SPECT-CT
Localization of parathyroid glands in hyperparathyroidism associated with MEN1. Sestamibi sensitivity ~35% in familial hyperparathyroidism with 4-gland hyperplasia [496,497]. 4D-CT has 60%–87% sensitivity [499]. For prolonged surveillance, radiation-free studies preferred.
Transthoracic echocardiogram (TTE)
Evaluation for carcinoid heart disease (CHD). Should include morphologic evaluation of valves (especially tricuspid and pulmonary), right heart size and function, and agitated saline injection if valve disease present to assess for atrial shunt [NE-B 2 of 5].
Biomarkers
5-HIAA (24-hour urine or plasma)
Serotonin metabolite for monitoring carcinoid syndrome. Predictive role for mortality [135]. Decreasing levels indicate treatment response; increasing levels indicate treatment failure.
Chromogranin A
Elevated in >60% of NET patients [238-240]. Associated with prognosis at levels ≥2× upper normal limit (HR, 2.8; 95% CI, 1.9–4.0; P < .001) [241]. Not recommended for routine follow-up for type 1 gastric NETs after baseline. Use limited by false elevations from PPIs, renal/hepatic impairment, and chronic gastritis.
Tumor-specific hormonal markers (gastrin, insulin, glucagon, VIP, somatostatin)
For functional PanNETs, follow-up with hormonal markers as clinically indicated for symptomatic monitoring and treatment response assessment.
Circulating tumor cells (CTCs)
Investigational biomarker. Presence of ≥1 CTC in 7.5 mL of blood independently associated with worse PFS and OS in patients with pretreated metastatic NETs [93].
NETest (multigene blood-based biomarker)
Blood-based test measuring multiple neuroendocrine gene transcripts. Demonstrated high sensitivity (>95%) in well-differentiated metastatic NETs [83]. Not impacted by PPI use unlike chromogranin A. Panel did not include in algorithm pending formal validation studies [MS-6].
StagingClick to collapse
AJCC 8th/9th edition TNM staging systems (Version 9, 2023 for GI and pancreatic NETs; Version 9, 2024 for lung and thymus; 8th edition, 2017 for adrenocortical carcinoma and PCC/PGL)
T Categories
| Stage | Description |
|---|---|
| T1 (Jejunal/Ileal NET) | Tumor invades mucosa or submucosa, and ≤1 cm in greatest dimension |
| T2 (Jejunal/Ileal NET) | Tumor invades muscularis propria or >1 cm in greatest dimension |
| T3 (Jejunal/Ileal NET) | Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |
| T4 (Jejunal/Ileal NET) | Tumor invades visceral peritoneum (serosal) or other organs or adjacent structures |
| T1 (Duodenal/Ampulla NET) | Tumor invades mucosa or submucosa only and ≤1 cm (duodenal); ≤1 cm and confined within sphincter of Oddi (ampullary) |
| T2 (Duodenal/Ampulla NET) | Tumor invades muscularis propria or >1 cm (duodenal); invades through sphincter into duodenal submucosa/muscularis propria or >1 cm (ampullary) |
| T3 (Duodenal/Ampulla NET) | Tumor invades the pancreas or peripancreatic adipose tissue |
| T4 (Duodenal/Ampulla NET) | Tumor invades the visceral peritoneum (serosa) or other organs |
| T1 (Appendiceal NET) | Tumor ≤2 cm in greatest dimension |
| T2 (Appendiceal NET) | Tumor >2 cm but ≤4 cm in greatest dimension |
| T3 (Appendiceal NET) | Tumor >4 cm in greatest dimension, or with subserosal invasion, or involvement of the mesoappendix |
| T4 (Appendiceal NET) | Tumor perforates the peritoneum, or directly invades other adjacent organs or structures (excluding direct mural extension to adjacent subserosa of adjacent bowel) |
| T1 (Colon/Rectum NET) | Tumor invades mucosa or submucosa and ≤2 cm; T1a ≤1 cm, T1b >1–≤2 cm |
| T2 (Colon/Rectum NET) | Tumor invades muscularis propria, or is >2 cm in greatest dimension with invasion of the mucosa or submucosa |
| T3 (Colon/Rectum NET) | Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |
| T4 (Colon/Rectum NET) | Tumor invades the visceral peritoneum (serosa), or other organs or adjacent structures |
| T1 (Gastric NET) | Tumor invades mucosa or submucosa and ≤1 cm in greatest dimension |
| T2 (Gastric NET) | Tumor invades muscularis propria or >1 cm in greatest dimension |
| T3 (Gastric NET) | Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |
| T4 (Gastric NET) | Tumor invades visceral peritoneum (serosa) or other organs or adjacent structures |
| T1 (Pancreatic NET) | Tumor limited to the pancreas, ≤2 cm in greatest dimension |
| T2 (Pancreatic NET) | Tumor limited to the pancreas, >2 cm but ≤4 cm in greatest dimension |
| T3 (Pancreatic NET) | Tumor limited to the pancreas, >4 cm in greatest dimension; or tumor invading the duodenum, ampulla of Vater, or common bile duct |
| T4 (Pancreatic NET) | Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery/vein, splenic artery/vein, gastroduodenal artery/vein, portal vein) |
| T1 (Lung NET) | Tumor ≤3 cm; subcategories T1a (≤1 cm), T1b (>1–≤2 cm), T1c (>2–≤3 cm) |
| T2 (Lung NET) | Tumor >3 cm but ≤5 cm; subcategories T2a (>3–≤4 cm), T2b (>4–≤5 cm) |
| T3 (Lung NET) | Tumor >5 cm but ≤7 cm, or ≤7 cm with invasion of parietal pleura/chest wall, pericardium, phrenic nerve, azygos vein, thoracic nerve roots, stellate ganglion, or separate tumor nodule(s) in the same lobe |
| T4 (Lung NET) | Tumor >7 cm, or tumor of any size invading mediastinum, thymus, trachea, carina, recurrent laryngeal nerve, vagus nerve, esophagus, diaphragm, heart, great vessels, subclavian vessels, vertebral body, spinal canal, cervical nerve roots, brachial plexus, or separate tumor nodule(s) in a different ipsilateral lobe |
| T1a/T1b (Thymic NET) | T1a: ≤5 cm, limited to thymus/encapsulation/mediastinal fat/mediastinal pleura only. T1b: >5 cm, same extent. |
| T2 (Thymic NET) | Direct invasion of pericardium (partial or full thickness), or lung, or phrenic nerve |
| T3 (Thymic NET) | Direct invasion into brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries or veins |
| T4 (Thymic NET) | Direct invasion into aorta (ascending, arch, descending), arch vessels, intrapericardial pulmonary artery or veins, myocardium, trachea, esophagus |
| T1 (Adrenocortical Carcinoma) | Tumor ≤5 cm, no extra-adrenal invasion |
| T2 (Adrenocortical Carcinoma) | Tumor >5 cm, no extra-adrenal invasion |
| T3 (Adrenocortical Carcinoma) | Tumor of any size with local invasion but not invading adjacent organs/surrounding tissues |
| T4 (Adrenocortical Carcinoma) | Tumor of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, liver) or large blood vessels (renal vein or vena cava) |
| T1 (PCC/PGL) | Pheochromocytoma <5 cm, no extra-adrenal invasion |
| T2 (PCC/PGL) | Pheochromocytoma ≥5 cm or sympathetic paraganglioma of any size, no extra-adrenal invasion |
| T3 (PCC/PGL) | Tumor of any size with local invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys) |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No tumor involvement of regional lymph node(s) |
| N1 (GI/Pancreatic NETs) | Tumor involvement of regional lymph node(s) |
| N1 (Jejunal/Ileal NET) | Tumor involvement of fewer than 12 regional lymph nodes |
| N2 (Jejunal/Ileal NET) | Tumor involvement of large mesenteric masses (>2 cm) and/or extensive nodal deposits (≥12 regional lymph nodes), especially those encasing the superior mesenteric vessels |
| N1 (Lung NET) | Tumor involvement of ipsilateral peribronchial and/or ipsilateral hilar and/or ipsilateral intrapulmonary lymph node station(s), including involvement by direct extension |
| N2 (Lung NET) | Tumor involvement of ipsilateral mediastinal nodal station(s) and/or subcarinal lymph node station; N2a = single ipsilateral mediastinal station or subcarinal; N2b = multiple ipsilateral mediastinal stations |
| N3 (Lung NET) | Tumor involvement of contralateral mediastinal, contralateral hilar, ipsilateral/contralateral scalene, or ipsilateral/contralateral supraclavicular lymph node station(s) |
| N1 (Thymic NET) | Tumor involvement of anterior (perithymic) lymph nodes |
| N2 (Thymic NET) | Tumor involvement of deep intrathoracic or cervical lymph nodes (e.g., paratracheal, subcarinal, aortopulmonary window, hilar, jugular, supraclavicular) |
| N1 (ACC/PCC/PGL) | Regional lymph node metastasis |
M Categories
| Stage | Description |
|---|---|
| M0 / cM0 | No distant metastasis |
| M1 / cM1 | Distant metastasis |
| M1a (GI/Pancreatic NETs) | Metastasis confined to liver |
| M1b (GI/Pancreatic NETs) | Metastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone) |
| M1c (GI/Pancreatic NETs) | Both hepatic and extrahepatic metastases |
| M1a (Lung NET) | Metastasis in pleural or pericardial nodules, and/or malignant pleural or pericardial effusions, and/or separate tumor nodule(s) in a contralateral lobe |
| M1b (Lung NET) | Single extrathoracic metastasis in a single organ system (including a single non-regional node) |
| M1c1 (Lung NET) | Multiple extrathoracic metastases in a single organ system |
| M1c2 (Lung NET) | Multiple extrathoracic metastases in multiple organ systems |
| M1a (Thymic NET) | Separate pleural or pericardial nodule(s) |
| M1b (Thymic NET) | Pulmonary intraparenchymal nodule or other distant metastasis |
| M1a (PCC/PGL) | Distant metastasis to only bone |
| M1b (PCC/PGL) | Distant metastasis to only distant lymph nodes/liver or lung |
| M1c (PCC/PGL) | Distant metastasis to bone plus multiple other sites |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage I | Jejunal/Ileal: T1 N0 M0; Duodenal/Ampulla: T1 NX/N0 M0; Appendix: T1 NX/N0 M0; Colon/Rectum: T1 NX/N0 M0; Stomach: T1 NX/N0 M0; Pancreas: T1 N0 M0; ACC: T1 N0 M0; PCC/PGL: T1 N0 M0 | Localized tumor with limited invasion and no nodal or distant metastases. Generally favorable prognosis with surgical resection. | 92% (PanNETs, institutional data [71]); 100% (jejunal-ileocecal NETs [53]); 75%–95% for ACC depending on risk factors | Curative surgical resection |
| Stage II | Jejunal/Ileal: T2-T3 N0 M0; Duodenal/Ampulla: T2-T3 N0 M0; Appendix: T2-T3 NX/N0 M0; Colon/Rectum: T2 NX/N0 M0 (Stage IIA), T3 N0 M0 (Stage IIB); Stomach: T2-T3 N0 M0; Pancreas: T2-T3 N0 M0; ACC: T2 N0 M0; PCC/PGL: T2 N0 M0 | Larger or more invasive tumor without nodal or distant metastases. Still potentially curative with resection. | 84% (PanNETs [71]); 100% (jejunal-ileocecal NETs [53]) | Curative surgical resection |
| Stage III | Jejunal/Ileal: T4 N0 M0 or Any T N1-N2 M0; Duodenal/Ampulla: T4 N0 M0 or Any T N1 M0; Appendix: T4 N0 M0 or Any T N1 M0; Colon/Rectum: T4 N0 M0 (Stage IIIA) or Any T N1 M0 (Stage IIIB); Stomach: T4 N0 M0 or Any T N1 M0; Pancreas: T4 N0 M0 or Any T N1 M0; Lung: T4 N0 M0 or T3-T4 N1 M0 (IIIA) etc.; ACC: T1-T2 N1 M0 or T3-T4 Any N M0; PCC/PGL: T1-T2 N1 M0 or T3 Any N M0 | Locally advanced disease with nodal involvement or deep invasion. May be resectable with multimodal approach. | 81% (PanNETs [71]); 91% (jejunal-ileocecal NETs [53]); 50%–76% (ACC stage III [21]) | Multimodal: surgery ± systemic therapy ± RT |
| Stage IV | All sites: Any T, Any N, M1 | Distant metastatic disease. Goals of treatment shift to palliation, symptom control, and extending survival. | 57% (PanNETs [71]); 72% (jejunal-ileocecal NETs [53]); 19.5% (PanNETs, SEER data [73]); <10% (ACC [21]); 63% at 5 years for PCC/PGL [442] | Palliative: systemic therapy, liver-directed therapy, cytoreduction as appropriate |
| Stage IVA (Lung NET) | Any T, Any N, M1a-M1b | Metastatic disease limited to contralateral lung/pleural/pericardial sites or single extrathoracic metastasis | Varies by histology and extent of metastatic disease | Systemic therapy, observation if low burden |
| Stage IVB (Lung NET) | Any T, Any N, M1c1-M1c2 | Multiple extrathoracic metastases in single or multiple organ systems | Generally poor; dependent on histology and burden | Systemic therapy, clinical trials |
Staging Pearls
- Multiple tumors in GI NETs should be designated as such; the largest tumor is used to assign T category (e.g., pT3(4) N0 M0 or pT3(m) N0 M0) [ST-1]
- Mesenteric masses ≤2 cm in jejunal/ileal NETs should be stated in the pathology report but do not affect stage [ST-1 N footnote]
- N2 category in jejunal/ileal NETs specifically includes large mesenteric masses >2 cm and/or extensive nodal deposits ≥12, especially those encasing superior mesenteric vessels — this is unique to small bowel NET staging [ST-1]
- Extrapulmonary NECs (including MiNENs) arising in any site are staged according to organ-specific criteria for their non-neuroendocrine carcinoma counterparts (e.g., adenocarcinoma or squamous carcinoma), NOT by NET-specific staging [MS-5, reference 76]
- For lung NETs, the staging system is the same as for more common lung carcinomas, incorporating both carcinomas and bronchopulmonary carcinoid (neuroendocrine) tumors [ST-6 to ST-10]
- For thymic NETs, staging is based on thymus-specific TNM criteria, not the lung system [ST-11 to ST-12]
- Parasympathetic paragangliomas are not staged because they are largely benign [ST-15 footnote]
- PCC/PGL staging is for pheochromocytoma/sympathetic paraganglioma only; parasympathetic PGLs are not staged [ST-15]
- ACC staging uses the 8th edition AJCC system and incorporates histologic grade (LG ≤20 mitoses/10 HPF; HG >20 mitoses/10 HPF or TP53/CTNNB mutations) [ST-16]
- Ki-67 index and mitotic rate should both be reported; when discordant, the higher value determines grade classification [NE-E 2 of 4]
- Ki-67 is preferred over mitotic rate for grading unless there is insufficient tissue [NE-E 2 of 4]
- Functional status is a clinical diagnosis, not a pathologic one — presence of hormone-staining granules without a clinical syndrome does not make a tumor 'functioning' [MS-6]
- Well-differentiated G3 NETs (Ki-67 >20%, well-differentiated morphology) have intermediate prognosis compared to PDNECs and G1-G2 NETs; median OS of 41–99 months vs. 17 months for PDNECs [356,357]
- Ki-67 threshold of 55% may better classify patients for response to platinum-based chemotherapy in high-grade GI NEC [51]; evolving data suggest Ki-67 20%–55% G3 NETs may not respond as well to platinum/etoposide as those with Ki-67 >55%
Management PrinciplesClick to collapse
Neuroendocrine tumors (NETs) encompass a broad family of neoplasms arising from the diffuse endocrine system, including well-differentiated NETs (G1/G2/G3), poorly differentiated neuroendocrine carcinomas (PDNECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). These guidelines address sporadic and hereditary neuroendocrine and adrenal tumors, with treatment approaches guided by tumor site of origin, histologic differentiation, grade/proliferation rate, stage, somatostatin receptor (SSTR) status, and hormonal functional status. Appropriate diagnosis and treatment often involves collaboration between specialists in multiple disciplines including pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. The incidence of NENs has increased significantly over recent decades, with the 20-year forecasted prevalence estimated at 243,896 individuals in the United States as of January 2021 [5]. Well-differentiated NETs comprise a spectrum from low-grade (G1) to high-grade (G3), with prognosis varying by stage, grade, and primary site. Patients with NETs may present with symptoms of hormonal hypersecretion ('functional' tumors) or without such symptoms ('nonfunctional' tumors). All recommendations are category 2A unless otherwise indicated.
Curative
Patients with localized, resectable disease across all NET subtypes, including GI, lung, thymic, pancreatic, and adrenal primary tumors
Surgical resection is the mainstay of curative intent treatment. For most localized NETs, complete surgical resection with adequate regional lymph node dissection (including all palpable disease where feasible) is recommended. Specific procedures vary by primary site: anatomic resection with mediastinal lymph node dissection for lung NETs; partial or total gastrectomy with regional lymphadenectomy for type 3 gastric NETs; bowel resection with lymphadenectomy for small bowel NETs; endoscopic resection for selected duodenal and rectal NETs; and site-specific pancreatic surgery for PanNETs. For adrenocortical carcinoma, achieving R0 resection is of critical importance and these operations should be performed by surgeons with high-volume experience in adrenal surgery [NE-D 2 of 3]. There is no established role for adjuvant therapy outside of clinical trials for NETs, although adjuvant mitotane therapy can be considered for high-risk adrenocortical carcinoma [NE-G 1 of 11, AGT-5].
Palliative/Control
Patients with locoregional unresectable or metastatic disease, including both functional and nonfunctional tumors
Treatment focuses on controlling tumor growth, managing hormonal symptoms, and maintaining quality of life. Somatostatin analogs (octreotide acetate LAR or lanreotide) serve dual purposes: symptom control for functional tumors and antiproliferative effects for SSTR-positive tumors. The PROMID trial demonstrated an antiproliferative effect of octreotide acetate LAR in advanced midgut NETs [158], and the CLARINET trial showed similar benefits with lanreotide in advanced well-differentiated GEP-NETs [160]. For tumors with clinically significant progression, molecularly targeted therapies (everolimus, sunitinib, cabozantinib), peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, and locoregional therapies (liver-directed therapy, radiation therapy) are employed. The choice of therapy considers tumor biology, SSTR status, Ki-67 index, tumor burden, patient performance status, and prior treatment history.
Adjuvant
Patients with resected adrenocortical carcinoma at high risk for recurrence
There is no established role for adjuvant systemic therapy in NETs outside of clinical trials. For adrenocortical carcinoma, adjuvant mitotane therapy can be considered for patients at high risk for local recurrence based on features including positive margins, Ki-67 >10%, rupture of capsule, large size, and high grade. Mitotane blood levels should be monitored with target levels of 14–20 mcg/mL if tolerated. Life-long hydrocortisone ± fludrocortisone replacement is usually required. The role of adjuvant chemotherapy is under investigation in the ongoing ADIUVO-2 study (NCT03583710) [NE-G 8 of 11, AGT-5]. Adjuvant external beam radiation therapy to the tumor bed can also be considered if concern exists regarding tumor spillage or close margins after surgery [AGT-5].
Multidisciplinary discussion is recommended for all patients with neuroendocrine and adrenal tumors. A multidisciplinary approach is essential for treatment planning, particularly for complex presentations including unresectable locoregional disease, metastatic disease, functional tumors requiring hormonal management, and hereditary syndromes requiring genetic counseling. Specific multidisciplinary discussions are recommended prior to biopsy of pancreatic NETs [PanNET-3 footnote l], for management of large (>2 cm) type 3 gastric NETs [NET-1], for ampullary duodenal NETs [NE-C 3 of 6], and for patients with well-differentiated Grade 3 NETs with unfavorable biology [WDG3-2]. For patients with carcinoid syndrome, invasive procedures should only be performed in centers with experienced anesthesiologists [NE-K 1 of 3]. The Panel acknowledges that unusual patient scenarios (presenting in <5% of patients) are not specifically discussed in these guidelines.
Performance status is a critical consideration in treatment selection for neuroendocrine and adrenal tumors. Patients with good performance status are candidates for aggressive multimodal approaches including surgical resection, cytoreductive surgery, and combination systemic therapies. For patients with resectable locoregional disease, surgery is recommended if the patient can tolerate the procedure. For metastatic disease, treatment considerations include performance status alongside tumor biology, burden of disease, and rate of growth. Cytoreductive surgery of >90% of metastatic disease may provide symptomatic relief, prevent future symptoms, and improve progression-free survival, particularly for patients with relatively indolent metastatic small bowel NETs [NE-D 2 of 3]. For adrenocortical carcinoma, patients who undergo splenectomy should receive vaccination against encapsulated bacteria [NE-D 2 of 3]. Patients with PCCs/PGLs require appropriate alpha-adrenergic blockade with volume repletion for 7–14 days prior to surgical therapy [PHEO-2]. For patients with other life-limiting comorbidities or high surgical risk, observation may be appropriate for small, indolent tumors [PanNET-2].
Management PathwaysClick to collapse
Branching: primary site (gastric, duodenal, appendiceal, jejunal/ileal/colon, rectal, lung, thymus), tumor size, tumor grade, lymph node status, disease stage, gastrin type (for gastric NETs), functional status
Branching: resectability of metastases, tumor burden, functional status, SSTR status, disease progression, site of disease
Branching: tumor burden, disease grade (typical vs atypical carcinoid), disease progression, symptoms, SSTR status
Branching: tumor size, tumor grade, functional status, germline VHL status, clinical scenario (nonfunctioning, gastrinoma, insulinoma, glucagonoma, VIPoma)
Branching: resectability of metastases, tumor burden, functional status, SSTR status, disease progression, Ki-67 index, germline VHL status
Branching: tumor biology (favorable vs unfavorable), Ki-67 index, SSTR status, growth rate
Branching: resectability, tumor burden, SSTR status, disease progression
Branching: Ki-67 index, SSTR status, disease progression
Branching: functional status, surgical candidacy, tumor burden, disease progression
Branching: resectability, disease site, molecular alterations (MSI-H, dMMR, TMB-H, NTRK, BRAF, RET)
Branching: functional status, surgical candidacy
Branching: symptoms, tumor burden, growth rate, SSTR status, RET fusion status
Branching: resectability, risk of local recurrence
Branching: resectability after systemic therapy, functional status, tumor burden
Branching: tumor grade (G1/G2 vs G3), primary site identified vs not identified
Branching: calcium levels, age, parathyroid gland involvement
Branching: bilateral vs unilateral, disease stage
Pretreatment EvaluationClick to collapse
Imaging - Anatomic
Imaging - Functional (SSTR-based)
Biochemical Evaluation
Pathology
Genetic Counseling
Cardiac Assessment
SurgeryClick to collapse
Surgical resection is the primary curative treatment for localized NETs and plays an important role in cytoreduction for selected patients with metastatic disease. For most localized NETs, complete surgical resection with adequate regional lymph node dissection is recommended. Cytoreductive surgery of >90% of metastatic disease may provide symptomatic relief, prevent future symptoms, and improve progression-free survival, particularly for patients with relatively indolent metastatic small bowel NETs [NE-D 2 of 3].
Resection of GI NETs should include adequate regional lymph node resection (including all palpable disease where feasible). Palpate the small bowel from the ligament of Treitz to the ileocecal valve [NE-D 1 of 3]
Gastric, duodenal, and rectal NETs may be endoscopically resectable [NE-C]
Standard oncologic surgery (distal pancreatectomy/splenectomy or pancreatoduodenectomy) is appropriate for most resectable, non-metastatic PanNETs [NE-D 1 of 3]
For non-functional PanNETs <2 cm, individualized decisions based on tumor characteristics and patient factors are recommended. Grade 1 PanNETs <2 cm can be safely observed; Grade 2 PanNETs should be considered for surgical resection [NE-D 1 of 3]
After simple appendectomy, if tumor >2 cm and positive lymph nodes in specimen, complete staging imaging and right hemicolectomy recommended [NE-D 1 of 3]
Assess implications of pancreatoduodenectomy in metastatic disease - usually not curative and impacts liver-directed therapy long-term [NE-D 1 of 3]
In setting of metastatic disease, resection of ileum/jejunum NETs should be performed when symptoms arise or to reduce future obstruction, mesenteric ischemia, bleeding, or perforation [NE-D 2 of 3]
Cholecystectomy is recommended when performing surgery for advanced NETs in patients anticipated to receive long-term SSAs due to higher risk of biliary symptoms [NE-D 2 of 3]
Prophylactic octreotide is likely ineffective in preventing intraoperative carcinoid crisis. Intraoperative octreotide administration should not delay vasopressor use and fluid administration [NE-D 2 of 3, NE-K 1 of 3]
For patients with clinical stage I or II ACC, achieving R0 resection is of critical importance. Operations should be performed by surgeons with high-volume experience. Open approach typically advised [NE-D 2 of 3]
Procedures
Lobectomy or other anatomic resection with mediastinal node dissection/sampling
Localized and resectable lung NETs. Sublobar resection may yield similar outcomes even for atypical carcinoids if tumor can be resected completely [NE-D 1 of 3, NET-6]
Partial or total gastrectomy with regional lymphadenectomy
Type 3 (sporadic) gastric NETs, type 1 or 2 gastric NETs >2 cm [NET-1]
Pancreatoduodenectomy (Whipple procedure)
PanNETs of the pancreatic head, duodenal/periampullary NETs not amenable to endoscopic/local excision, gastrinomas of the pancreatic head [NE-D 1 of 3]
Distal pancreatectomy with or without splenectomy
PanNETs of the pancreatic body or tail [NE-D 1 of 3]
Tumor enucleation
Exophytic or peripheral insulinomas, selected small PanNETs [NE-D 1 of 3, PanNET-6]
Bowel resection with regional lymphadenectomy
Jejunal/ileal/colon NETs [NET-4, NE-D 1 of 3]
Right hemicolectomy
Appendiceal NETs >2 cm, or any size with incomplete resection or positive lymph nodes [NET-3]
Low anterior resection or abdominoperineal resection
Rectal NETs T2–T4 or node positive [NET-5]
Minimally invasive adrenalectomy
Benign adrenal tumors, PCCs (preferred when safe and feasible), small ACC (explore with minimally invasive with planned conversion if invasion suspected) [AGT-3, AGT-4, PHEO-2]
Open adrenalectomy
Suspected ACC, large adrenal tumors (>4 cm with malignant features), locally invasive disease. May require removal of adjacent structures [AGT-4, AGT-5, NE-D 2 of 3]
Subtotal or cortical-sparing adrenalectomy
MEN2-associated PCCs with bilateral tumors, hereditary PCC/PGL syndromes with appreciable risk for bilateral tumors [NE-F 5 of 6, MEN2-1]
Cytoreductive hepatectomy
Liver metastases from NETs where >90% cytoreduction is feasible, particularly for symptomatic patients or those with relatively indolent disease [NE-D 2 of 3]
Parathyroidectomy (subtotal or total with autotransplantation)
MEN1-associated hyperparathyroidism, MEN2A-associated hyperparathyroidism [MEN1-2, MEN2-1]
Radiation TherapyClick to collapse
External beam radiation therapy (EBRT) is a useful modality for select patients with locoregional or metastatic neuroendocrine or adrenal tumors. Decisions to use EBRT should be made in a multidisciplinary manner, considering patient factors, disease site/stage, and other therapeutic options available [NE-I 1 of 2].
Principles
- EBRT may be considered for any histologic subtype of NETs (including well-differentiated G1/2/3, NECs, MiNENs, PCCs, and PGLs) [NE-I 1 of 2]
- Site-specific principles used for other primary cancer types are generally applicable [NE-I 1 of 2]
- Higher EBRT doses have been associated with higher rates of disease control, but may be associated with increased risk of adverse events [3], [NE-I 1 of 2]
- IMRT/VMAT techniques with IGRT may be needed to maintain precision and reduce toxicity [NE-I 1 of 2]
- When administering SBRT/SABR, IGRT techniques and motion management are strongly recommended [NE-I 1 of 2]
- EBRT generally does not play a role in locoregional NETs of small bowel, appendix, or colon (including mesenteric disease) due to risk of bowel injury. However, focal EBRT may be considered in select circumstances [NE-I 1 of 2]
- EBRT may be considered in locoregional NETs of lung, thymus, and GI tract locations where resection may have significant morbidity [NE-I 1 of 2]
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Stereotactic Body Radiation Therapy (SBRT)/Stereotactic Ablative Radiotherapy (SABR) | Varies by site and organ tolerance | High dose per fraction | ≤5 fractions | Daily or every other day | Oligometastatic disease at multiple sites including liver, adrenal, bone, lung, mediastinum, head and neck, and lymph nodes; liver-limited metastases with <5 lesions [NE-I 1 of 2] |
| Hypofractionated RT | Varies | Moderate dose per fraction | 6–20 fractions | Daily | Most frequently used regimen for functional NETs to improve hormonal symptoms [NE-I 1 of 2] |
| Conventional fractionation with concurrent chemotherapy | Varies by site | Standard dose per fraction | Varies | Daily with concurrent radiosensitizing chemotherapy | Locoregional unresectable disease, particularly for atypical carcinoid histology or tumors with higher Ki-67 [NET-11] |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Palliative RT for symptomatic bone metastases | Hypofractionated (≤10 fractions) preferred | None | Painful bone metastases, impending pathologic fracture, or cord compression [NE-I 1 of 2] | Not specified | Fatigue, local pain, possible vertebral compression fracture |
| Liver-directed EBRT (SBRT/SABR) | ≤5 fractions, ablative dose | None | Limited (<5) liver metastases. May be used alone or in combination with other liver-directed therapies [NE-I 1 of 2] | Not specified | Radiation-induced liver disease, fatigue, nausea |
| RT ± concurrent fluoropyrimidine-based chemotherapy for locally advanced unresectable disease | Varies | Fluoropyrimidine-based (eg, capecitabine) | Locally advanced unresectable disease in GI NETs and PanNETs (excluding small bowel mesenteric); locally advanced unresectable lung/thymic NETs [NET-10, NET-11, PanNET-13] | Not specified | Site-specific toxicities, chemotherapy-related toxicity |
| RT ± concurrent Cisplatin/Etoposide or Carboplatin/Etoposide | Standard fractionation | Cisplatin/Etoposide or Carboplatin/Etoposide | Locoregional unresectable intermediate-grade (atypical carcinoid) lung/thymic NETs. Thought to have greatest efficacy in tumors with atypical histology or higher Ki-67 [NET-11] | Not specified | Esophagitis, pneumonitis, myelosuppression |
| Definitive chemoradiation for NEC | Standard fractionation | Cisplatin + etoposide or carboplatin + etoposide | Resectable extrapulmonary poorly differentiated NECs when definitive chemoradiation is selected instead of surgery [PDNEC-1] | Not specified | Myelosuppression, mucositis, esophagitis, nausea/vomiting |
Systemic TherapyClick to collapse
Systemic therapy for neuroendocrine tumors encompasses somatostatin analogs, molecularly targeted therapies (everolimus, sunitinib, cabozantinib), peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, and immunotherapy. Treatment selection is guided by tumor site of origin, histologic grade, SSTR status, Ki-67 index, disease burden, disease progression, performance status, and prior treatment history. There is no known role for systemic treatment in the adjuvant setting for NETs [NE-G 1 of 11]. Currently, there are no data to support a specific sequence of regional versus systemic therapy, and no data to guide sequencing of systemic therapy options [NE-G 1 of 11]. Doses and schedules are subject to appropriate modifications depending on the circumstances.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Treatment Response Assessment and Surveillance
Timing
For resected NETs: 12 weeks to 12 months post-resection (earlier if symptomatic), then every 12–24 months for up to 10 years. For advanced/metastatic disease: every 12 weeks to 12 months based on clinical or pathologic signs of aggressiveness. SSTR-based imaging should be repeated at time of progressive disease on cross-sectional imaging [NET-8, PanNET-11, NE-B 1 of 5]
Response Logic
-
Multiphasic (dual-phase) contrast-enhanced CT is important for monitoring liver metastases as NETs frequently enhance in arterial phase [NE-B 1 of 5]
-
SSTR-PET/CT should be repeated at the time of progressive disease on cross-sectional imaging to reassess SSTR status [NET-8]
-
Consider same imaging modality and contrast agent for follow-up studies for consistent imaging interpretation [NE-B 1 of 5]
-
For functional tumors, biochemical markers (5-HIAA for carcinoid syndrome, specific hormone markers) should be followed as clinically indicated [NET-8]
-
Chromogranin A monitoring is not routinely recommended due to challenges with reproducibility and interference from PPIs and comorbidities [NE-A 1 of 4]
-
For carcinoid syndrome, echocardiogram should be performed every 1–3 years or as clinically indicated for patients without CHD, and at least annually for patients with established CHD [NET-14, NE-B 2 of 5]
-
For resected ACC: Every 12 wk–12 mo up to 10 y (after 10 y as clinically indicated) with chest CT ± contrast and abdomen CT or MRI with contrast, and biomarkers if tumor initially functional [AGT-5]
-
For resected PCC/PGL: H&P, blood pressure, and markers annually or sooner if symptomatic, for up to 10 years [PHEO-3]
-
After 10 years post-resection, surveillance should be considered as clinically indicated. Data are limited on optimal surveillance beyond 10 years [NET-8, NE-B 2 of 5]
Imaging Recommendations
-
Primary GI NETs: Multiphasic abdomen ± pelvis CT or MRI, chest CT ± contrast as clinically indicated [NET-8]
-
Primary lung/thymic NETs: Chest CT + multiphasic CT or MRI abdomen with contrast, pelvis CT or MRI with contrast as clinically indicated [NET-8]
-
SSTR-based imaging and FDG-PET/CT are not recommended for routine surveillance [NET-8, PanNET-11]
-
For metastatic disease monitoring: consider same imaging modality for consistent interpretation [NE-B 1 of 5]
Biopsy Or Salvage Logic
-
In select cases, resection may be considered for recurrent locoregional disease, isolated distant metastases, or previously unresectable tumor that has regressed [NET-8]
-
For patients with disease progression on SSA therapy, consider switching to alternative first-line systemic therapy [NET-12, PanNET-13]
-
Consider enrollment in clinical trials at time of disease progression
-
For suspected carcinoid heart disease, cardiology consultation recommended [NET-14]
Molecular Pathogenesis Gastric NetsClick to collapse
The molecular pathogenesis of gastric NETs varies by subtype and is not fully elucidated. Type 1 gNETs arise due to chronic hypergastrinemia secondary to autoimmune or H. pylori-induced atrophic gastritis, leading to loss of acid feedback and ECL-cell hyperplasia, which can progress to dysplasia and neoplasia. This process is driven by gastrin trophic effects, but specific driver mutations are not well-defined. Type 2 gNETs are associated with gastrinomas, often in MEN1 syndrome, where inactivating mutations in the MEN1 gene (encoding menin) on chromosome 11q13 lead to loss of tumor suppression, resulting in gastrin-secreting tumors and subsequent ECL-cell hyperplasia. Sporadic type 3 gNETs may involve mutations in genes such as CDKN1B (encoding p27, a cyclin-dependent kinase inhibitor), which has been identified in small bowel carcinoid tumors and could contribute to uncontrolled cell growth. Other somatic mutations reported in sporadic pancreatic NETs (e.g., in DAXX, ATRX, and mTOR pathway genes like PIK3CA, PTEN) may also play a role, but specific data for gastric NETs are limited. PPI-induced gNETs likely result from sustained hypergastrinemia due to acid suppression, but their indolent nature suggests additional molecular differences from sporadic tumors. Epigenetic changes, such as DNA methylation, and alterations in signaling pathways (e.g., Wnt, Notch) are areas of ongoing research. Immunohistochemical markers like synaptophysin, chromogranin A, and INSM1 confirm neuroendocrine differentiation, but they are not predictive of pathogenesis. Overall, the molecular landscape is heterogeneous, and further studies are needed to clarify driver events in each subtype. [References: NCCN Guidelines v1.2026, Discussion MS-7, MS-51, NE-E 1 of 9, References 10, 91]
Risk Factors Gastric NetsClick to collapse
Risk factors for gastric NETs are primarily linked to the underlying etiology of each subtype. For type 1 gNETs, the main risk factors include chronic atrophic gastritis (autoimmune or H. pylori-related), which leads to hypergastrinemia and ECL-cell hyperplasia. Conditions such as pernicious anemia, autoimmune disorders, and H. pylori infection are associated with increased risk. For type 2 gNETs, the presence of gastrinoma (Zollinger-Ellison syndrome) is the key risk factor, often in the context of MEN1 syndrome, which has a strong hereditary component. Type 3 gNETs are sporadic, and no specific environmental risk factors are well-established, though a family history of NETs or other neuroendocrine neoplasias may increase susceptibility. PPI-induced gNETs are associated with long-term use of proton pump inhibitors (typically >1 year), which causes hypergastrinemia and ECL-cell stimulation; however, the risk appears low and depends on the duration and dosage of PPI therapy. Other potential risk factors mentioned in general NET literature include obesity, diabetes, and smoking, but these are not specifically validated for gastric NETs. Genetic predispositions include germline mutations in MEN1 (for type 2 and some sporadic cases), and possibly other genes like SDHx, though data are limited. The strength of evidence varies: for chronic atrophic gastritis and PPI use, evidence is moderate based on observational studies; for MEN1 and gastrinomas, evidence is strong due to well-defined syndromes; for sporadic risk factors, evidence is weak and largely based on case-control studies. [References: NCCN Guidelines v1.2026, NET-1, Discussion MS-10, MS-11, References 132, 133]
Protective Factors Gastric NetsClick to collapse
No specific protective factors for gastric NETs are explicitly mentioned in the source text. The risk is primarily driven by pathological conditions (e.g., chronic gastritis, gastrinoma) or iatrogenic factors (e.g., PPI use), rather than modifiable protective factors. General measures that might reduce risk include early detection and management of H. pylori infection to prevent atrophic gastritis, but this is not directly stated as protective. Similarly, judicious use of PPIs may mitigate the risk of PPI-induced gNETs, but evidence is limited. Overall, the source does not identify any evidence-based protective factors. [References: NCCN Guidelines v1.2026]