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NEUROENDOCRINE TUMORS OF SMALL BOWEL

Small Bowel Neuroendocrine Tumors (NETs)

Origin and Historical Context

  • Arise from: Enterochromaffin cells (Kulchitsky cells/Argentaffin cells), which are neural crest cells located at the base of the crypts of Lieberkühn.
  • Arise from not ectoderm but from endodermal origin
  • Historical figures:
    • Lubarsch, 1888
    • Oberndorfer, 1907
  • Most common locations: Lungs, bronchi, appendix, and small bowel.
  • Age of occurrence: Most commonly in the 7th decade of life.

Anatomical Location

  • Small bowel NETs almost always occur within the last 2 feet of the ileum.

Serotonin (5-HT) and Other Secretory Products Based on Tumor Location

Tumor Location Serotonin (5-HT) Other Secretory Products
Foregut Low 5-HTP/ACTH
Midgut High -
Hindgut Very Low Somatostatin, Peptide YY

Pathology

  • Carcinoid syndrome: Mostly seen in liver metastases.
  • Metastatic rates:
    • 3% in appendiceal NETs.
    • 35% in ileal NETs.
  • Malignant potential depends on:
    • Location.
    • Size.
    • Depth of invasion.
    • Growth pattern.
  • Multicentric (multiple tumors) in 20%-30% of cases.
  • Synchronous adenocarcinoma: Occurs in 10%-20% of small bowel NET cases, with the colon being the most common site.
  • Association with MEN-1: Seen in 10% of cases.

Clinical Features

  • 70%-80% of cases: Asymptomatic.
  • Most common symptom: Abdominal pain.
  • Malignant carcinoid syndrome: Seen in <10% of patients, associated with ovarian and retroperitoneal NETs.
    • Cutaneous flushing: 80%.
    • Diarrhea: 76%.
    • Hepatomegaly: 71%.
    • Cardiac lesions: Right-sided heart valvular disease (41%-70%).
    • Asthma: 25%.
    • Pellagra.
  • Varieties of cutaneous flushing in carcinoid syndrome:
    1. Diffuse erythematous.
    2. Violaceous.
    3. Prolonged flushes.
    4. Bright-red patchy flushing.

Diagnosis

  • 24-hour urinary levels of 5-HIAA:
    • Highly specific, but not sensitive.
  • Chromogranin A (CgA):
    • Elevated in 80% of NETs.
    • Specificity: 95%.
    • Sensitivity: 55%.
  • NETs of the small intestine: Rarely diagnosed preoperatively.
  • Imaging studies:
    • Small bowel barium studies.
    • CT/MRI.
    • Sensitivity of imaging:
      • 68Ga-DOTATATE: 95%.
      • 18FDG PET/CT: 37%.

Table 49-9: Secretory Products of Neuroendocrine Tumors

Category Secretory Products
Amines - 5-HT (Serotonin)
- 5-HIAA (88%)
- 5-HTP
- Histamine
- Dopamine
Tachykinins - Kallikrein
- Substance P (32%)
- Neuropeptide K (67%)
Peptides - Pancreatic polypeptide (40%)
- Chromogranins (100%)
- Neurotensin (19%)
- HCG-α (28%)
- HCG-β
- Motilin (14%)
Others - Prostaglandins

Table 49-10: Medical Therapies for Neuroendocrine Tumor Treatment

Therapy Type Details
Approved Therapeutics
- Somatostatin analogues: Octreotide (Sandostatin, Sandostatin LAR), Lanreotide (Somatuline depot)
- Cytotoxic therapies: Streptozotocin (for pancreatic NET only)
- mTOR inhibitor: Everolimus (Afinitor; for pancreatic NET only)
- Tyrosine kinase inhibitors: Sunitinib (Sutent; for pancreatic NET only)
Used Off-Label
- Pan-receptor somatostatin agonists: Pasireotide (Signifor; approved for Cushing's disease only)
- Interferons: Interferon alfa, Interferon alfa-2b
- Cytotoxic therapies: 5-Fluorouracil (5-FU), Cyclophosphamide (Cytoxan), Temozolomide (Temodar), Capecitabine (Xeloda)
Investigational
- Peptide receptor radionuclide therapy: - 90Y conjugated with somatostatin analogues
- 177Lu isotopes conjugated with somatostatin analogues
- Serotonin synthesis inhibitors: Telotristat etiprate (LX1032/LX1606)
- VEGF inhibitors: Bevacizumab (Avastin)
- Dopamine agonists: Dopastat

MCQs with Explanations

1. Gut neuroendocrine cells arise from?

  • a. Ectoderm
  • b. Neural crest cells
  • c. Mesoderm
  • d. Endoderm

Explanation: Gut neuroendocrine cells, such as enterochromaffin cells, arise from neural crest cells. These cells migrate during development to various parts of the body, including the gut.

2. D cells secreting Somatostatin are located in all except?

  • a. Duodenum
  • b. Pancreas
  • c. Stomach
  • d. Jejunum

Explanation: D cells are primarily located in the duodenum, pancreas, and stomach. They are not typically found in the jejunum.

3. Neuropeptide Y is secreted by?

  • a. N cells
  • b. L cells
  • c. I cells
  • d. PP cells

Explanation: L cells are responsible for secreting Neuropeptide Y along with other hormones like GLP-1.

4. Neuroendocrine tumors arise from?

  • a. Interstitial cells of cajal
  • b. Argentaffin cells
  • c. Paneth cells
  • d. Brunner's cells

Explanation: Neuroendocrine tumors arise from argentaffin cells (also called Kulchitsky cells), which are specialized cells in the gut.

5. All are true regarding NET except?

  • a. First described by Lubarsh in 1888
  • b. In 1907, Oberndorfer coined the term Karzinoide
  • c. Most common site in GI tract is small bowel
  • d. Most common in lungs & bronchi

Explanation: While neuroendocrine tumors (NETs) can occur in various locations, the lungs and bronchi are one of the most common sites, not the small bowel, which is more common in GI NETs.

6. All are true about NET of small bowel except?

  • a. In small intestine, NETs almost always occur within the last 2 feet of the ileum
  • b. Foregut NETs characteristically produce low levels of serotonin
  • c. Midgut NETs are characterized by having low serotonin production
  • d. Hindgut NETs rarely produce serotonin

Explanation: Midgut NETs typically produce high levels of serotonin, especially in cases of small bowel NETs.

7. All are true regarding small bowel NET except?

  • a. Small bowel NETs are multicentric in 20% to 30% of patients
  • b. Synchronous adenocarcinoma can occur in 10% to 20% of patients with small bowel NET
  • c. Multiple endocrine neoplasia type 1 is associated with NETs in approximately 40% of cases
  • d. The most common symptom is abdominal pain

Explanation: The association of MEN-1 with NETs is around 10%, not 40%.

8. Malignant potential of a NET is related to all except?

  • a. Tumor location
  • b. Tumor size
  • c. Tumor grade
  • d. Growth pattern

Explanation: While tumor grade does play a role, it is not the primary factor. Tumor location, size, and growth pattern are the key indicators for the malignant potential.

9. All are true statements regarding malignant carcinoid syndrome except?

  • a. Seen in <10% of patients
  • b. Mostly seen in ovarian and retroperitoneal NETs
  • c. Cutaneous flushing is the most common symptom
  • d. Left-sided valvular heart diseases are common

Explanation: Right-sided valvular heart disease is more common in malignant carcinoid syndrome, not left-sided.

10. All are true regarding malignant carcinoid syndrome except?

  • a. The diarrhea associated with carcinoid syndrome is episodic
  • b. Asthmatic attacks are usually observed during the flushing
  • c. Left-sided cardiac lesions are common
  • d. Malabsorption and pellagra are associated

Explanation: Right-sided cardiac lesions are more common, not left-sided.

11. All are true regarding NET except?

  • a. Elevated 24-hr urinary levels of 5-HIAA highly specific and sensitive
  • b. Chromogranin A (CgA), is elevated in 80% of NET, with specificity 95%, sensitivity 55%
  • c. NETs of the small intestine are rarely diagnosed preoperatively
  • d. Sensitivity of DOTATATE scan is ~97%

Explanation: While 24-hr urinary 5-HIAA is highly specific, it is not highly sensitive.

12. All are true regarding treatment of carcinoid of small bowel except?

  • a. Tumors of D4 are treated by resection anastomosis
  • b. For small bowel lesions, wide excision of bowel and mesentery is required
  • c. Lesions of the terminal ileum are best treated by segmental resection
  • d. Small duodenal tumors can be excised locally

Explanation: Lesions of the terminal ileum require a wider resection including bowel and mesentery, not just a segmental resection.

13. All are true regarding prognosis of small bowel NET except?

  • a. NETs have the best prognosis of all small bowel tumors
  • b. Resection of a NET localized to its primary site approaches a 100% survival rate
  • c. 5-year survival rates are 65% with regional disease and 25%-35% in those with distant metastasis
  • d. An elevated level of Chromogranin-A is not a prognostic indicator

Explanation: Chromogranin-A is a significant prognostic indicator. Elevated levels of CgA are associated with a worse prognosis.

14. Which of the following drug is not an approved medication in the medical management of NET of small bowel?

  • a. Streptozotocin
  • b. Sunitinib
  • c. Lanreotide
  • d. Bevacizumab

Explanation: Bevacizumab (an anti-VEGF agent) is investigational and not approved for routine use in NETs. Streptozotocin, Sunitinib, and Lanreotide are approved medications.

15. Which of the following is an amine secretory product of NET secreted in the highest quantity?

  • a. 5-HIAA
  • b. Chromogranin A
  • c. Kallikrein
  • d. 5-HT

Explanation: 5-HT (Serotonin) is secreted in higher quantities compared to the other amine products like 5-HIAA and Kallikrein in NETs.

16. Elevated serum Chromogranin is seen in all except?

  • a. Renal failure
  • b. Inflammatory Bowel Disease (IBD)
  • c. Use of Proton Pump Inhibitors (PPIs)
  • d. Congestive cardiac failure

Explanation: Chromogranin-A can be elevated in renal failure, IBD, and PPIs usage, but is not typically elevated in congestive cardiac failure.

Gastric Carcinoids

Gastric Carcinoid Types:

  • Type I:
    • Associated with chronic atrophic gastritis and pernicious anemia.
    • Located in the fundus or body of the stomach.
    • Most common type, accounting for 75% of gastric carcinoids.
    • Tumors are typically small, multiple, and well-differentiated.
    • Best prognosis among all types of gastric carcinoids.
  • Type II:
    • Due to excessive gastrin production secondary to Zollinger-Ellison Syndrome (ZES).
    • Also seen in patients with MEN1 (Multiple Endocrine Neoplasia Type 1).
    • Located in the fundus, body, or antrum of the stomach.
    • Accounts for 5% of gastric carcinoids.
    • Tumors are well-differentiated, small, and multiple.
    • Can have metastasis.
  • Type III:
    • Makes up 20% of gastric carcinoids.
    • Typically presents as a solitary, large tumor.
    • Located in the fundus or antrum of the stomach.
    • Not associated with hypergastrinemia.
    • Often has metastasis and has the worst prognosis.
    • Produces 5-hydroxytryptophan.
  • Type IV:
    • Presents as a solitary large tumor.
    • Associated with parietal cell hyperplasia.
    • Can be located anywhere in the stomach.
    • Types 1-3 are most commonly found in the body and fundus.

All are true about Type I gastric carcinoid except?

  • a. Well differentiated
  • b. Multiple tumors
  • c. Associated with hypergastrinemia
  • d. Most common in antrum

Answer: d. Most common in antrum

Explanation:

  • Type I Gastric Carcinoid is commonly associated with chronic atrophic gastritis and pernicious anemia. These tumors typically arise in the fundus or body of the stomach, not the antrum. They make up about 75% of gastric carcinoids.
  • Key characteristics of Type I gastric carcinoids:
    • Well differentiated: The tumors are typically small and well-differentiated.
    • Multiple tumors: They are often multiple.
    • Associated with hypergastrinemia: The hypergastrinemia is secondary to the underlying chronic gastritis.
    • Location: They are most commonly found in the fundus or body, not the antrum.

Thus, the correct answer is d. Most common in antrum, as Type I gastric carcinoids are primarily located in the fundus or body.