Neuroendocrine Tumors

A

Demographics

• 1.

  Incidence is rising, likely because of increased detection; the majority are found in the gastrointestinal (GI) tract and pancreas.

• 2.

  Peak incidence is in sixth to seventh decade of life.

B

Classification (Multiple Systems and Evolving Terminology)

• 1.

  Histologic: well differentiated (previously known as carcinoid tumors) versus poorly differentiated (G3) (previously known as neuroendocrine carcinomas)

• 2.

  Well-differentiated neuroendocrine tumors (NETs) can be further subgrouped into low (G1) and intermediate grade (G2) by mitotic rate (<2 mitoses/10 high-power field [hpf] vs. 2–20 mitoses/10 hpf) or Ki67 labeling index (<3% vs. 3%–20%).

C

Location

• 1.

  Majority originate from enterochromaffin cells in GI tract.

• 2.

  Other locations include bronchopulmonary tract, larynx, pancreas (islet cell tumors), biliary tract, thymus, ovary, kidney, and skin.

D

Presentation

• 1.

  This varies depending on physical characteristics, origin, and if hormones are produced.

• 2.

  Ninety percent of patients are hormonally asymptomatic; hormonal products must obtain direct access to the systemic circulation (hepatic metastases, significant retroperitoneal disease, primary tumor not draining to portal venous circulation) to be active and not cleared by liver.

• 3.

  Mass of tumor can cause intussusception or obstruction (e.g., small bowel obstruction [SBO], jaundice, appendicitis, pancreatitis).

• 4.

  Hormone secretion can cause carcinoid symptoms, such as:

  • a.

    Flushing—bradykinin, hydroxytryptophan, prostaglandins

  • b.

    Diarrhea—serotonin

  • c.

    Cramping—serotonin

  • d.

    Endocardial fibrosis—serotonin

  • e.

    Pellagra—depletion of niacin stores due to serotonin

  • f.

    Bronchospasm—bradykinin, histamine, prostaglandins

  • g.

    Telangiectasia—vasoactive intestinal peptides, serotonin, prostaglandins, bradykinin

  • h.

    Glucose intolerance—serotonin

  • i.

    Arthropathy—serotonin

  • j.

    Hypotension—serotonin

• 5.

  Symptoms can be induced by consumption of ethanol, chocolate, or blue cheese and by exertion and surgery.

• 6.

  Metastatic potential is related to grade, location, and size.

• 7.

  Urinary 5-hydroxyindoleacetic acid, serum chromogranin A, and substance P are most commonly measured.

E

Staging and Localization

• 1.

  Chest computed tomography (CT) scan—bronchial NET

• 2.

  Endoscopy/endoscopic ultrasound (EUS)—ability to biopsy gastric, duodenal, distal small ileal NETs, colorectal carcinoids, and pancreas

• 3.

  Multiphasic CT scan and/or CT enterography—liver metastases, retroperitoneal masses, and carcinomatosis

• 4.

  Nuclear medicine scans (pentetreotide indium-111, gallium Ga-68 Dotatate positron emission tomography [PET] scan, and MIBG [metaiodobenzylguanidine I123])

• 5.

  Angiography/selective venous sampling—may be useful in difficult cases

F

Management

• 1.

  Appendiceal

  • a.

    Less than 1 cm, low grade without mesoappendix invasion and negative margin—appendectomy

  • b.

    One to 2 cm—controversial because risk of metastases is rare, particularly if smaller than 1.5 cm

  • c.

    Greater than 2 cm or other higher risk factors for lymphatic metastases in good-risk patient—right hemicolectomy

• 2.

  Small bowel (more likely to metastasize)

  • a.

    Multicentric in 20%–40%—must examine all of small bowel and colon

  • b.

    Resection of involved small bowel and mesentery; can consider cholecystectomy if somatostatin analogs are likely to be used in future

• 3.

  Rectal

  • a.

    Less than 1 cm, T1, low grade—endoscopic/transanal excision

  • b.

    One to 2 cm, low grade controversial

  • c.

    Greater than 2 cm, T2 or other higher-risk factors, low anterior resection (LAR) or abdominoperineal resection (APR) to resect and clear draining nodes

• 4.

  Gastric

  • a.

    Type 1 associated with chronic atrophic gastritis and achlorhydria: endoscopic resection of small tumors and surveillance, antrectomy for progression to reduce gastrin secretion or more radical resection for more advanced disease

  • b.

    Type 2 associated with gastrinoma: treat primary

  • c.

    Type 3 sporadic NET not in association with chronic atrophic gastritis: partial or total gastrectomy and regional node resection

• 5.

  Metastatic disease

  • a.

    Observation in asymptomatic patients with very slow progression

  • b.

    Systemic therapy

    • (1)

      Somatostatin analogs, both for symptoms and for tumor growth

    • (2)

      Molecular therapies targeting mechanistic target of rapamycin (mTOR), thymidine kinase (TK), or vascular endothelial growth factor (VEGF), such as everolimus, sunitinib, bevacizumab

    • (3)

      Interferon-α

    • (4)

      Radiolabeled somatostatin analogs

    • (5)

      Cytotoxic chemotherapy, particularly for high-grade or rapidly growing cancers

  • c.

    Surgical intervention

    • (1)

      Obstruction, perforation, bleeding, or other tumor-related symptoms

    • (2)

      Potentially resectable disease

    • (3)

      Severe carcinoid symptoms for which sufficient debulking anticipated with low morbidity

  • d.

    Regional intraarterial therapy

  • e.

    Radiofrequency or stereotactic body radiation therapy (SBRT) ablative therapies

A

Demographics

• 1.

  This is found in 0.1% of individuals with duodenal ulcers and 2% of individuals with ulcers refractory to medical therapy.

• 2.

  Twenty-five percent of gastrinomas are associated with multiple endocrine neoplasia syndrome type 1 (MEN1).

• 3.

  Gender distribution is 60% male, 40% female.

• 4.

  Mean onset of symptoms is before sixth decade of life.

B

Location

• 1.

  Eighty-five percent of gastrinomas are located in the gastrinoma triangle, more commonly in duodenum than in pancreas itself ( Fig. 52.1 ).

  

• 2.

  Ectopic locations include splenic hilum, gastric wall, mesentery, and liver.

C

Presentation

• 1.

  Symptoms are secondary to hypergastrinemia; increased gastrin leads to acid hypersecretion by parietal cells and peptic ulceration.

• 2.

  Abdominal pain and diarrhea are most common symptoms.

  • a.

    It may be caused by ulcers that 90% of individuals have endoscopically confirmed in the upper GI tract.

  • b.

    Ulcers may also lead to bleeding (30%–50%) and perforation (5%–10%).

  • c.

    Diarrhea presents as only symptom in 20% of cases. It is caused by acid hypersecretion, injury to small bowel mucosa, malnutrition caused by inactivated enzymes, and increased motility.

• 3.

  Gastroesophageal reflux

D

Diagnosis

• 1.

  Serum gastrin level

  • a.

    Increased in 90% of patients (reference range, 100–200 pg/mL)

  • b.

    Fasting serum gastrin level greater than 1000 pg/mL in presence of gastric acid diagnostic

  • c.

    For serum gastrin levels 200–1000 pg/mL, secretin stimulation testing can distinguish gastrinomas from G-cell hyperplasia

• 2.

  Localization

  • a.

    Endoscopy/EUS, multiphasic CT, or magnetic resonance imaging (MRI)

  • b.

    Somatostatin receptor scintigraphy or Ga-68 Dotatate PET/CT

    • (1)

      Most gastrinomas have somatostatin receptors.

    • (2)

      False-negative rate for small duodenal wall gastrinomas is high.

  • c.

    Angiography with selective arterial secretin stimulation and venous sampling

  • d.

    Intraoperative

E