Neuroendocrine Tumors (NETs) of the GI Tract

1. Overview and Cell of Origin

• Current Surgical Therapy 14e, p. 190
• Sleisenger and Fordtran's GI and Liver Disease

2. Epidemiology and Distribution

• At presentation: 40% have multifocal tumors >2 cm; 70% have muscularis propria/lymph node invasion; 50% have liver metastasis
• 5-year survival: local disease ~95%, nodal disease ~84%, distant disease ~51% (overall ~32% with distant disease)

3. WHO Classification (2019/2022)

• Current Surgical Therapy 14e, WHO 2017 classification
• Sleisenger and Fordtran, Table 34.2A & 34.2B

4. Specific Tumor Types and Their Syndromes

A. Carcinoid Tumors (Non-functional/functional midgut NETs)

B. Carcinoid Syndrome

• Tryptophan → 5-HTP → (aromatic L-amino acid decarboxylase) → 5-HT (serotonin) → stored in platelets → converted to 5-HIAA (excreted in urine)

Clinical Features:

• Flushing: In gastric NETs, caused by histamine (prevented by H1+H2 antihistamines); other mediators include tachykinins (substance P), bradykinins
• Carcinoid heart disease: Right-sided valvular lesions (tricuspid regurgitation, pulmonary stenosis) from serotonin depositing fibrous plaques on right heart valves
• Diagnosis: Elevated 24-hour urinary 5-HIAA is the gold standard
• Sleisenger and Fordtran, Table 34.11

C. Gastrinoma (Zollinger-Ellison Syndrome)

• Source: G-cells (gastrin-secreting), primarily in duodenum and pancreas
• Most common pNET in MEN-1 patients (almost always duodenal in MEN-1)
• Zollinger-Ellison triad: Refractory peptic ulcers + hypersecretion of gastric acid + non-beta islet cell tumor
• Presents with severe/recurrent PUD, diarrhea, esophagitis
• Diagnosis: Fasting serum gastrin >1000 pg/mL (or >200 with low gastric pH) + secretin stimulation test (paradoxical rise in gastrin)

D. Insulinoma

• Most common functional pNET
• Whipple's triad: Hypoglycemic symptoms + blood glucose <50 mg/dL + relief with glucose
• Diagnosis: 72-hour fast; plasma insulin-to-glucose ratio >0.3; inappropriately elevated C-peptide; elevated proinsulin

• 90% are benign and solitary

• Imaging: Multiphasic CT, EUS; Ga-68 DOTATATE PET only if metastases suspected

E. VIPoma (Verner-Morrison Syndrome / WDHA)

• Secretes Vasoactive Intestinal Polypeptide (VIP)
• WDHA syndrome: Watery Diarrhea + Hypokalemia + Achlorhydria (pancreatic cholera)
• Large volume secretory diarrhea (>3L/day)

F. Glucagonoma

• Secretes glucagon → hyperglycemia + catabolism
• Classic: "4 Ds" - Dermatitis (necrolytic migratory erythema), Diabetes, Deep vein thrombosis, Depression
• Necrolytic migratory erythema is pathognomonic - migratory, crusting rash on legs/perineum
• Usually large and malignant at diagnosis

G. Somatostatinoma

• Inhibits multiple GI functions
• Inhibitory triad: Diabetes mellitus (inhibits insulin) + Steatorrhea/cholelithiasis (inhibits CCK/pancreatic enzymes) + Hypochlorhydria (inhibits gastrin/acid)
• Rare; most are pancreatic or duodenal

5. Inherited Syndromes Associated with GI-NETs

• Sleisenger and Fordtran, Table 34.3

6. Diagnosis and Imaging

Biochemical Markers

• Chromogranin A - universal marker for all NETs (elevated in >80%)
• Urinary 5-HIAA - carcinoid syndrome (sensitivity 70-75%, specificity >90%)
• NSE (neuron-specific enolase) - particularly for poorly differentiated NETs
• Specific hormones (gastrin, insulin/C-peptide, VIP, glucagon, somatostatin) for functional tumors

Imaging

• CT/MRI: First-line; NETs are hyperenhancing on arterial phase (unlike adenocarcinomas)
• Ga-68 DOTATATE PET scan: Somatostatin receptor scintigraphy - most sensitive for localization and staging of well-differentiated NETs (>90% express somatostatin receptors). Preferred over older In-111 octreoscan
• EUS (endoscopic ultrasound): Best for small pancreatic and duodenal lesions
• Hepatic venous sampling after arterial calcium stimulation: Rarely needed; used when imaging fails to localize insulinoma

7. Management

Surgery

• Curative intent: Wide en bloc resection with mesenteric lymphadenectomy for small bowel NETs
• Inspect for multicentric disease (40% are multifocal) and liver metastases
• Even with liver metastases, resect primary for local control and symptom relief
• Debulking: Aim to remove >90% of tumor burden for durable symptomatic relief
• Carcinoid crisis (during operative manipulation): Hemodynamically significant surge in vasoactive peptides - managed with high-dose IV somatostatin analogues + hemodynamic support

Medical Management

• Somatostatin analogues (octreotide, lanreotide): First-line for symptom control in carcinoid syndrome; block release of serotonin and tachykinins; prevent flushing in 20-30%, diarrhea in 50-60%; also have antiproliferative effect (PROMID, CLARINET trials)
• Telotristat ethyl (tryptophan hydroxylase inhibitor): Added for refractory diarrhea despite SSA therapy
• mTOR inhibitors (everolimus): For progressive well-differentiated pNETs and GI-NETs
• Sunitinib: For advanced well-differentiated pNETs
• PRRT (Peptide Receptor Radionuclide Therapy with Lu-177 DOTATATE): For somatostatin receptor-positive advanced/metastatic NETs refractory to SSA
• Streptozocin-based chemotherapy: Primarily for poorly differentiated NECs
• PPIs: High-dose for gastrinoma (ZES)

Liver Metastases

• Hepatic resection if >90% debulking achievable
• Liver-directed therapies: TACE (transarterial chemoembolization), hepatic artery embolization, radiofrequency ablation
• Liver transplantation in highly selected patients with unresectable liver-only disease

8. Prognosis by Location

• Appendiceal NETs <2 cm: Almost never metastasize; simple appendectomy curative
• Rectal NETs <1 cm: Very low metastatic potential; local endoscopic resection sufficient
• Small bowel NETs: Indolent but high rate of nodal/hepatic spread at diagnosis
• Poorly differentiated NECs: Highly aggressive; similar to SCLC behavior; treated with platinum-etoposide