What is the appropriate diagnostic and treatment approach for a patient presenting with symptoms suggestive of a Pancreatic Neuroendocrine Tumor (pNET) or a Gastrointestinal Neuroendocrine Tumor (GI NET)?

Diagnostic and Treatment Approach for Pancreatic and GI Neuroendocrine Tumors

When a patient presents with symptoms suggestive of a pNET or GI NET, immediately obtain plasma chromogranin A and 24-hour urinary 5-HIAA as baseline tests, followed by histological confirmation through biopsy, which is mandatory for diagnosis. 1

Initial Biochemical Workup

Baseline laboratory testing:

• Plasma chromogranin A (CgA) - serves as a general NET marker, particularly useful in gastric carcinoids with metastases 1
• 24-hour urinary 5-HIAA - essential for detecting carcinoid syndrome, raised in 70% of midgut NETs 1
• Additional general markers: calcium, thyroid function tests, PTH, calcitonin, prolactin, CEA, AFP, and β-HCG 1

Critical pitfall: CgA can be falsely elevated by proton pump inhibitors, renal failure, and atrophic gastritis—do not rely on it alone for diagnosis 2. In poorly differentiated G3 tumors, CgA is often normal; consider NSE as an alternative marker 1.

Syndrome-specific testing based on clinical presentation:

• Gastrinoma: Fasting gastrin with gastric secretion studies 1
• Insulinoma: Fasting insulin, glucose, C-peptide (with negative sulphonylurea screen) 1
• Glucagonoma: Fasting gut hormones and skin biopsy 1
• VIPoma: Fasting vasoactive intestinal peptide 1
• Carcinoid syndrome: Tachykinins (neurokinin A and B) if 5-HIAA is equivocal 1

Important dietary restrictions before 5-HIAA collection: Avoid bananas, avocados, eggplant, pineapple, plums, walnuts, paracetamol, fluorouracil, methysergide, naproxen, and caffeine—all cause false positives 1.

Histological Confirmation

Histopathology is mandatory in all cases and should be obtained via endoscopic biopsy, surgical specimen, or ultrasound-guided core needle biopsy from the primary or metastatic site 1, 3.

Required immunohistochemical staining:

• Pan-neuroendocrine markers: Chromogranin A and synaptophysin (both must be positive) 1
• Ki-67 proliferation index - absolutely essential for WHO grading and treatment selection 1, 2
• Hormone-specific staining (serotonin, gastrin, insulin, glucagon) only confirms the source of symptoms but does not prove functionality 1

WHO 2010 Classification based on Ki-67:

• NET G1: Ki-67 ≤2% 1, 4
• NET G2: Ki-67 3-20% 1, 4
• NEC G3: Ki-67 >20% 1, 4

Imaging Strategy

For detecting the primary tumor, use a multimodality approach:

First-line imaging:

• Gallium-68 PET/CT - most sensitive modality for detecting unknown primaries and staging 1
• If Ga-68 PET/CT unavailable, use somatostatin receptor scintigraphy (SSRS) combined with CT 1
• Contrast-enhanced CT or MRI of abdomen/pelvis for anatomical localization and liver metastases 1, 2, 3

Additional modalities when needed:

• Endoscopic ultrasound (EUS) for pancreatic and gastric primaries 1
• Upper endoscopy for gastric, duodenal, and proximal small bowel lesions 1
• Colonoscopy for colonic primaries 1
• Digital subtraction angiography (DSA) with venous sampling for localizing small functional tumors 1

Important caveat: Not all NETs express significant somatostatin type 2 receptors, so always complement nuclear imaging with CT or MRI 1.

Genetic and Syndromic Evaluation

Perform clinical examination and obtain detailed family history in all cases to exclude:

• Multiple Endocrine Neoplasia type 1 (MEN-1) - screen for parathyroid and enteropancreatic tumors from late childhood in affected families 1, 2
• Von Hippel-Lindau disease - patients may present 15-20 years earlier than sporadic cases 1

Suspect familial syndrome when: Family history of carcinoids/NETs exists, or patient has a second endocrine tumor 1.

Treatment Algorithm

For Localized Disease (No Metastases)

Surgery is the only curative treatment and first-line therapy for all resectable disease 1, 5.

Surgical approach:

• Formal pancreatectomy with lymph node sampling for most pNETs 5
• Enucleation only for small insulinomas 5
• Radical gastrectomy with lymph node dissection for resectable type III gastric NETs 2
• Consider cholecystectomy during abdominal surgery if long-term somatostatin analogue therapy is anticipated 1

Postoperative outcomes: 95% postoperative survival with 86% 3-year overall survival and 81% disease-free survival for non-metastatic pNETs 6.

Exception for observation: Small (<2 cm) nonfunctioning G1 tumors can be safely observed without immediate surgery 7.

For Metastatic Disease

Use a multimodal approach with 70% 3-year survival achievable 6.

Treatment sequence:

1. Cytoreductive surgery for resectable liver metastases or locoregional recurrences 5, 6

2. Liver-directed therapies:

   • Radiofrequency ablation (RFA) 5, 6
   • Transarterial chemoembolization (TACE) 5, 6
   • Hepatic chemoembolization 6

3. Systemic therapy based on tumor grade:

   • For G1/G2 with positive somatostatin receptors: Somatostatin analogues (octreotide, Sandostatin LAR) as first-line 5, 8, 7
   • For progressive G1/G2: Everolimus or sunitinib targeting mTOR and VEGF pathways 5, 8, 7
   • For poorly differentiated G3 neuroendocrine carcinomas: Cisplatin-etoposide chemotherapy 2
   • Peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-positive tumors 7

4. External beam radiotherapy for symptomatic bone metastases 1

Important note: Traditional cytotoxic chemotherapy has been largely ineffective for well-differentiated pNETs 5.

Multidisciplinary Team Management

All NETs must be discussed in a multidisciplinary tumor board including gastroenterologists, oncologists/endocrinologists, surgeons, radiologists, nuclear medicine specialists, histopathologists, and clinical nurse specialists 1, 2.

Referral to specialized centers is mandatory for definitive management guidance 1.

Surveillance and Follow-Up

For resected tumors:

• Serial chromogranin A measurements every 3-6 months for G1/G2 tumors 2
• CT or MRI every 3-6 months for NET G1/G2 2, 4
• Every 2-3 months for NEC G3 4
• SSRS may be indicated for follow-up after primary resection 1

Staging using TNM classification according to ENETS/UICC guidelines is crucial for prognosis, with 5-year survival of 50-70% for localized disease versus 20-30% for high-grade tumors 3.