What are the investigations and management options for a patient suspected of having neuroendocrine tumors (NETs)?

Investigations and Management of Neuroendocrine Tumors

Initial Biochemical Investigations

All patients suspected of having NETs should undergo baseline testing with plasma chromogranin A and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA). 1

• These baseline markers assist in diagnosis and provide prognostic information 1
• Chromogranin A is elevated in most NETs and serves as a general tumor marker 1
• 24-hour urinary 5-HIAA is particularly useful for midgut NETs, where it is elevated in 70% of patients 1

Syndrome-specific biochemical testing should be ordered based on clinical presentation: 1

• Gastrinoma: Fasting gastrin levels and gastric secretion studies (expect raised basal serum gastrin with high gastric acid secretion) 1
• Insulinoma: Fasting insulin, glucose, and C-peptide with negative sulphonylurea screen (expect raised insulin/glucose ratio) 1
• Glucagonoma: Fasting gut hormones and skin biopsy (expect raised pancreatic glucagon and enteroglucagon) 1
• VIPoma: Fasting vasoactive intestinal peptide (expect elevated levels) 1
• Carcinoid syndrome: 24-hour urinary 5-HIAA, particularly if flushing and diarrhea are present 1

Important caveats for 5-HIAA testing: Certain foods and medications cause false results. Avoid banana, avocado, aubergine, pineapple, plums, walnut, paracetamol, fluorouracil, methysergide, naproxen, and caffeine before collection (false positives). Levodopa, aspirin, ACTH, methyldopa, and phenothiazines cause false negatives. 1

Imaging Investigations

For detecting the primary tumor, use a multi-modality approach with CT, MRI, and somatostatin receptor scintigraphy (SSRS). 1

First-Line Imaging

• Gallium-68 PET/CT is the most sensitive imaging modality and is recommended for detecting unknown primaries 1
• Where Ga-68 PET/CT is unavailable, SSRS combined with CT is the most sensitive alternative 1
• Use multiphase technique CT or MRI for baseline imaging in suspected metastatic disease, as NETs are highly vascular and can appear isodense with liver on conventional CT 1

Site-Specific Imaging Approaches

Gastric, duodenal, and colonic NETs:

• Endoscopy (colonoscopy or esophagogastroduodenoscopy) as primary detection method 1
• CT scanning for staging 1

Pancreatic NETs:

• Endoscopic ultrasound (EUS) is a major diagnostic tool with sensitivity of 90-100% for pancreatic lesions 2, 3
• Combine CT, MRI, and EUS with SSRS for accurate localization 1
• Consider digital subtraction angiography (DSA) with intra-arterial calcium stimulation in select cases 1

Gastrinomas (special consideration):

• Perform upper gastrointestinal endoscopy and CT or MRI first, as 80% of gastrinomas in MEN1 are duodenal 2
• EUS sensitivity is lower for extrapancreatic gastrinomas compared to pancreatic lesions 2
• Intra-arterial calcium stimulation with DSA may be particularly important for localizing occult gastrinomas 2

Bronchopulmonary and thymic NETs:

• Chest CT is the best modality for lung lesions 1
• Bronchoscopy for centrally located bronchial lesions 1
• Follow with SSRS to assess full disease extent 1

Midgut NETs:

• May not be visible on standard imaging despite causing symptoms 1
• SSRS (octreoscan) and mesenteric angiography are useful when CT and barium studies are negative 1
• Look for characteristic "starburst" appearance with central calcification from desmoplastic reaction on CT 1

Additional Imaging Modalities

• Endoscopic ultrasound for pancreatic and duodenal NETs 1
• Digital subtraction angiography with venous sampling in select cases 1
• Proctoscopic examination for rectal NETs 1

Histopathological Confirmation

Histopathology is required to confirm the diagnosis before definitive treatment. 1

• Obtain tissue for WHO classification including immunohistochemical profile with neuroendocrine markers and Ki-67 proliferation index 3
• The pathology report must include tumor size, invasion depth, margin status, and proliferation indices 1, 3
• If histology is available from a previous primary site, biopsy of metastases may not be necessary 1

Genetic Evaluation

Perform clinical examination to exclude complex cancer syndromes, particularly MEN1, in all NET cases. 1

• Take a detailed family history in all patients 1
• In cases with family history of NETs or a second endocrine tumor, obtain a comprehensive familial history 1

Management Approach

Multidisciplinary Team Evaluation

All patients with NETs should be discussed in a multidisciplinary team at a referral center before definitive management. 1

• MDT should include specialist physicians (gastroenterologists, oncologists, endocrinologists), surgeons, radiologists, nuclear medicine specialists, histopathologists, and clinical nurse specialists 1

Treatment Strategy Based on Disease Stage

For localized, resectable disease:

• Surgery should be offered with curative intent to fit patients with limited disease confined to primary and regional lymph nodes 1, 3
• Complete removal of the primary tumor with negative margins and regional lymph node dissection is the goal 3
• Determine tumor extent, metastases, histological grade, and secretory profile before planning treatment 1

For metastatic disease:

• Surgery should be considered for potentially resectable liver metastases 1
• Noncurative debulking surgery can be considered in select cases, especially if symptomatic from tumor bulk or hormone production 1
• Resection of the primary site with unresectable metastases is generally not indicated unless the primary is symptomatic 1
• For small bowel primaries causing intermittent obstruction or ischemia from surrounding fibrosis, palliative resection is recommended 1

Medical Management

For carcinoid syndrome:

• Somatostatin analogues (octreotide or lanreotide) are first-line treatment for symptom control 1, 4
• Lanreotide 120 mg every 4 weeks is FDA-approved for carcinoid syndrome to reduce frequency of short-acting rescue therapy 4
• If already on lanreotide for GEP-NET, do not administer an additional dose for carcinoid syndrome 4

For progressive GEP-NETs:

• Lanreotide 120 mg every 4 weeks improves progression-free survival in unresectable, well- or moderately-differentiated, locally advanced or metastatic GEP-NETs 4
• Sunitinib 37.5 mg daily is FDA-approved for progressive pancreatic NETs, with median PFS of 10.2 months versus 5.4 months for placebo 5

Important medication monitoring:

• Monitor for cholelithiasis periodically with somatostatin analogues 4
• Check glucose levels regularly, as both hyperglycemia and hypoglycemia can occur 4
• Monitor for cardiovascular abnormalities including bradycardia 4
• Assess thyroid function where clinically indicated 4
• Evaluate for pancreatic exocrine insufficiency if new steatorrhea, stool discoloration, loose stools, or weight loss occur 4

Site-Specific Management Considerations

Rectal NETs:

• Tumors <1 cm have excellent prognosis and require no follow-up 1
• Tumors 1-2 cm require follow-up endoscopies with rectal MRI or EUS at 6 and 12 months, then as clinically indicated 1

Appendiceal NETs:

• Tumors ≤2 cm without aggressive features require follow-up only as clinically indicated 1
• Small, well-differentiated appendiceal NETs have very low recurrence risk 1

Type 1 and 2 gastric NETs (with hypergastrinemia):

• Follow-up endoscopies every 6-12 months for first 3 years, then annually if no progression 1
• Gastrin levels remain persistently high in type 1 gastric NETs with atrophic gastritis and are generally uninformative 1
• Consider antrectomy if new lesions or increasing tumor burden develops 1

Follow-Up Protocol

For resected disease:

• Regular follow-up with biochemical markers and conventional imaging every 3-6 months for G1/G2 tumors 3
• Somatostatin receptor imaging after 18-24 months if somatostatin receptor expression is confirmed 3
• Cross-sectional imaging (CT and MRI) using RECIST criteria may be indicated if patient is in a clinical trial 1
• SSRS is not routinely recommended for surveillance after definitive resection 1

Monitor for complications:

• Mesenteric fibrosis causing small bowel obstruction 3
• Carcinoid heart disease (tricuspid regurgitation/pulmonary stenosis) if carcinoid syndrome has been present for years 1, 3
• Carcinoid crisis risk with anesthetic induction, tumor manipulation, or invasive procedures 3