Appendiceal Neuroendocrine Tumor

Appendiceal neuroendocrine tumor (carcinoid of the appendix) is a well-differentiated neoplasm from enterochromaffin cells, and is the commonest tumor of the appendix. It is found in 0.3 to 0.9% of appendectomy specimens. Mean age is about 40 years, and women are more often affected than men. About 70% occur at the tip, 20% in the body and 10% at the base.

Grading by proliferation: grade 1 (Ki-67 under 3%), grade 2 (3 to 20%) and grade 3 (over 20%, rare and behaves aggressively). Size predicts behavior: tumors under 1 cm (about 75%) almost never metastasize, those of 1 to 2 cm have a nodal metastasis risk of up to about 10%, and tumors over 2 cm have a risk of about 30% or more with distant spread. Further risk features: base involvement, mesoappendiceal invasion over 3 mm, lymphovascular invasion, grade 2 histology, and goblet cell component.

Carcinoid syndrome is rare (under 1%) and only with liver metastases. Synchronous or metachronous second neoplasm (usually colorectal) occurs in about 15 to 20% of patients. Prognosis is excellent: 5-year survival is near 100% for localized disease and about 30 to 40% for distant metastases.

• Most are asymptomatic and found at appendectomy for appendicitis (tumors at the base can obstruct the lumen)
• Right iliac fossa pain, or an incidental mass
• Carcinoid syndrome with flushing, diarrhea, wheeze and right heart valve disease in metastatic disease
• Red flags: a tumor over 2 cm, positive margin at the base, lymphadenopathy, liver lesions and hormonal symptoms

1. Histology after appendectomy, with immunohistochemistry (chromogranin A, synaptophysin), Ki-67 index, tumor size, depth of invasion, margin status and lymphovascular invasion.
2. Staging for tumors over 2 cm, with risk features, or grade 2: CT of the chest, abdomen and pelvis with contrast, and somatostatin receptor imaging (gallium-68 DOTATATE PET-CT).
3. Biochemistry for suspected syndrome or metastatic disease: 24-hour urinary 5-hydroxyindoleacetic acid (normal under 47 micromol/24 h), plasma chromogranin A, and echocardiography for carcinoid heart disease.
4. Colonoscopy for synchronous neoplasia.

Differentials: goblet cell adenocarcinoma, mucinous neoplasm, appendiceal adenocarcinoma, metastasis, carcinoid of other sites.

1. Tumor under 1 cm, completely excised, no risk features: appendectomy is curative. No routine follow-up is needed.
2. Tumor 1 to 2 cm without risk features: appendectomy alone, with follow-up imaging.
3. Right hemicolectomy for:
   • Tumor over 2 cm
   • Tumor of 1 to 2 cm with base involvement, positive margin, mesoappendiceal invasion over 3 mm, lymphovascular invasion, or grade 2
   • Nodal involvement on imaging
   • Goblet cell features with high risk
4. Prophylaxis: cefazolin 2 g IV as a single dose before incision (3 g if over 120 kg), with metronidazole 500 mg IV as a single dose. Enoxaparin 40 mg SC once daily for 7 days after resection.
5. Metastatic or unresectable disease:
   • Octreotide long-acting 30 mg IM every 28 days or lanreotide 120 mg deep SC every 28 days for hormonal symptoms and tumor control.
   • Resection or ablation of liver metastases when feasible.
   • Peptide receptor radionuclide therapy with lutetium-177 dotatate 7.4 GBq IV every 8 weeks for 4 cycles, with a concurrent amino acid infusion (lysine and arginine 25 g each in 1 L over 4 hours) for renal protection.
   • Everolimus 10 mg orally once daily (monitor glucose, lipids, mouth ulcers and pneumonitis).
   • Grade 3 disease: platinum-based chemotherapy.
6. Carcinoid crisis prophylaxis before operation in patients with symptoms: octreotide 100 to 500 micrograms IV bolus before induction, and infusion of 50 to 100 micrograms/h.
7. Follow-up: CT or MRI annually for 5 to 10 years for patients with risk features or after hemicolectomy. Counsel about the second-neoplasm risk and screening colonoscopy.