Definition
- Small bowel tumour originating from enterochromaffin cells (neuroendocrine cells) in the gut epithelium. These tumors may produce: Serotonin, histamine, bradykinin, or tachykinins.
Epidemiology
- 9.3/1,000,000 (increasing – possibly due to better diagnosis)
- Account for 37% of small bowel malignant tumours
- Median age 67
Aetiology
Arise from Enterochromaffin cells (Kulchitsky cells) located in the Crypts of Lieberkühn
Clinical
- Clinical symptoms
- Episodic abdominal pain or borborygmi
- Carcinoid syndrome
- Intestinal bleeding is rare
- Bowel obstruction
- Carcinoid syndrome
- Term applied to a constellation of symptoms mediated by various humoral factor released from well-differentiated NETs.
- More than 90% of patients with carcinoid syndrome have metastatic disease from a small bowel primary NET - typically to the liver.
- Monoamine oxidase in the liver can generally detoxify substances - thus is patient symptomatic = liver metastasis.
- Can occur with very large retroperitoneal tumours
- Symptoms of carcinoid occur due to serotonin, tachykinins (substance P), prostaglandins, PDGF.
- Symptoms of carcinoid syndrome
- Secretory diarrhoea - often prevalent in the morning and often meal related.
- Cutaneous flushing - often provoked by stress, ETOH, certain food, cheese or coffee.
- Heart valve fibrosis - right side valvular fibrosis, can result in carcinoid heart disease - RHF.
- Other sections
- NETs can produce a number of different peptides
- Foregut – Low levels of serotonin but can produce 5-hydroxytryptophan and ACTH
- Midgut – High levels of serotonin
- Hindgut – Rarely produce serotonin but produce somatostatin and peptide YY
- Also produce corticotropin, histamine, dopamine, neurotensin, prostaglandins, kinins, gastrin, calcitonin
- 70-80% asymptomatic
Pathophysiology
- WHO classifies NENs
| Terminology | Differentiation | Grade | Mitotic rate* (mitoses/2 mm2) | Ki-67 index* (%) |
|---|---|---|---|---|
| NET, G1 | Well differentiated | Low | <2 | <3 |
| NET, G2 | Well differentiated | Intermediate | 2 to 20 | 3 to 20 |
| NET, G3 | Well differentiated | High | >20 | >20 |
| NEC, small cell type (SCNEC) | Poorly differentiated | HighΔ | >20 | >20 (often >70) |
| NEC, large cell type (LCNEC) | Poorly differentiated | HighΔ | >20 | >20 (often >70) |
| MiNEN | Well or poorly differentiated¶ | Variable¶ | Variable¶ | Variable¶ |
| LCNEC: large cell neuroendocrine carcinoma; MiNEN: mixed neuroendocrine-non-neuroendocrine neoplasm; NEC: neuroendocrine carcinoma; NET: neuroendocrine tumor; SCNEC: small cell neuroendocrine carcinoma. |
Mitotic rates are the number of mitoses/2 mm2 (ie, 10 high-power fields at 40× magnification and an ocular field diameter of 0.5 mm). To assess the mitotic rate, count in 50 fields of 0.2 mm2 (over a total area of 10 mm2). To assess the Ki-67 proliferation index, count at least 500 cells in the regions of highest labeling (using scanning magnification). The final grade is determined by the value (mitotic rate or Ki-67 proliferation index) that places the tumor in the category with the higher grade.
¶ In most MiNENs, both the neuroendocrine and non-neuroendocrine components are poorly differentiated. Additionally, the mitotic rate and Ki-67 proliferation index of the neuroendocrine component usually fall into the same range as an NEC. However, in some MiNENs, either (or both) components could be well-differentiated so they should be graded separately, if possible.
Δ Poorly differentiated NECs are not formally graded but are considered high grade by definition.
Location
- 90% are found in one of 5 sites
- 38% Appendix
- 29% Small bowel (usually within 2 feet of Ileocaecal valve)
- 13% Colon
- 12% Stomach
- 8% Rectum
- Metastasie
- Only 3% of Appendiceal NETs metastasise
- 35% Ileal NETs associated with metastasis
- Risk of metastasis also related to size
- 2% NETs < 1cm
- 50% NETs 1-2cm
- 80-90% NETs > 2cm
Investigation
- Bloods
- Chromogranin A – elevated in 80% of pts
- Sensitivity: 55%, Specificity: 95%
- Chromogranin A – elevated in 80% of pts
- Urine
- Elevated 5-HIAA (metabolic product of serotonin breakdown)
- 24h urine test
- When combined with serum chromogranin A, provides acceptable sensitivity and specificity
- Imaging
- CT
- Primaries often small and not seen on imaging
- Mesenteric lesions are classically spiculated with spoke-like appearance within mesentery due to local desmoplastic reaction
- CT-A useful for operative planning
- MRI generally does not provide additional information
- Can be used to look for liver lesions
- Octreotide scintigraphy can be used
- FDG PET only avid in high grade tumours
- Now DOTATATE PET/CT is more widespread, binds to somatostatin receptors
- CT
- Pre-op colonoscopy – 10-15% Synchronous Colorectal Adenoca
- ECHO to investigate for cardiac abnormalities
Management
Surgery
- Primary site
- Surgery most effective therapy when possible
- Small lesions (< 1cm) can be removed endoscopically or with segmental resection
- Larger lesions need wide excision of bowel and mesentery
- Significant anaesthetic issues
- Can develop Carcinoid Crisis – flushing, hypotension, bronchospasm, tachycardia
- Give octreotide intra-op if carcinoid crisis
- In the context of mets
- If symptomatic resect
- Consider resecting if resectable metastatic disease
- Liver metastasis
- Consider treating with metastectomy
- Traditionally considered if >90% of disease can be resected although limited evidence
- Improves symptoms
- If unable to resect
- Chemoembolization or radioembolization
- Aggressive debulking may prolong survival but requires extensive debulking to improve symptoms.
- High morbidity so medical mgmt of widespread disease more appropriate
- Consider treating with metastectomy
- Surgical technique
- The majority of metastasis originate from primary lesions in the terminal parts of the ileum, and tend to be deposited mainly on the right side of the mesenteric artery.
- To remove - often require mobilisation of the right colon and small bowel up to the pancreas and horizontal duodenum - this posterior view allows the vessels to be easily identified and divide the fibrotic surrounds to the mesenteric root.
- Generally the right colon requires removal.
- Bypass should be avoided - ischaemia may still develop of disengaged segment.
Medical
- Somatostatin analogue
- Long acting Octreotide or Lantreotide
- Can be used to relieve symptoms if symptomatic patients
- Decreases hormone release
- In patients with a high tumour burden
- Treats tumour growth
- Can be used to relieve symptoms if symptomatic patients
- Long acting Octreotide or Lantreotide
- Chemotherapy efficacy limited
- Peptide Receptor Radioligand Therapy (PRRT)
- Indications:
- Advanced (Metastatic) or Progressive disease despite long-acting somatostatin analog AND
- Somatostatin Receptor-Positive Disease AND
- No underlying Renal or Haematologic insufficiency
- Most commonly used radionuclides: Yttrium-90 (90Y) and Lutetium-177 (177Lu)
- Long-Term Adverse Effects:
- Renal impairment
- Pancytopaenia
- Myelodysplastic Syndrome
- Secondary Acute Leukaemia
- Evidence
- NETTER-1 trail https://www.nejm.org/doi/full/10.1056/NEJMoa1607427
- Indications:
- Liver directed therapy
- Last line
- TKi - Carbozantinib
- mTORi - Everolimus
- Transplant for NET
- UK criteria for NET (remains experimental)
- Grade 1 or 2
- Primary (inc nodes) completely resected
- No extrahepatic disease
- Less than 50% liver volume occupied by tumour
- Disease stability for >6 months
- UK criteria for NET (remains experimental)
Prognosis
- NETs best prognosis of all small bowel tumours
- Resection of localised tumour, close to 100% survival
- Regional disease 5 yr survival 65%
- Distant mets 5 yr survival 25-35%
- Metastases present in 20-50% at presentation
- Recurrence in 40-60%