Carcinoid tumor

Carcinoids are small, slow-growing neuroendocrine tumors. They are most commonly located in the gastrointestinal tract and can synthesize a variety of hormones (especially serotonin). Most carcinoids are asymptomatic because most of the hormones they produce are metabolized by the first-pass effect in the liver. Carcinoid syndrome – characterized by diarrhea, flushing, dyspnea, and wheezing – may occur if a serotonin-producing tumor has metastasized to the liver, bypassing first-pass metabolism. Elevated 5-HIAA in the urine helps to establish the diagnosis. Imaging techniques such as CT, MRI, and somatostatin receptor scintigraphy are used to detect the primary tumor as well as its metastases. Surgical resection is the first-line treatment. In inoperable cases, somatostatin analogs can be given.

• Incidence: 1.5/100,000 per year
• Bimodal distribution: peak incidence rates between 15 and 25 years and between 65 and 75 years ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Overview ^[2]

• Carcinoid tumors are neuroendocrine tumors that arise from amine precursor uptake and decarboxylation cells (APUD cells).
  • A group of endocrine cells that secrete peptide hormones (e.g., secretin, cholecystokinin)
  • These cells take up amine precursors (e.g., 5-hydroxytryptophan) and decarboxylate them to form amines.
• Neuroendocrine cells (including β cells in the pancreas or enterochromaffin cells in the GI tract) belong to the APUD series and share a common biologic function despite their different embryologic origins, anatomic sites, and secretory products (e.g., serotonin, histamine).

Tumor location ^[2]

• GI tract (55% of cases): carcinoid
  • Small intestine (esp. the ileum): 45%
  • Rectum: 20%
  • Appendix: 17%
  • Colon: 11%
  • Stomach: 7%
• Pancreas (15% of cases)
  • Insulinoma
  • Glucagonoma
• Bronchopulmonary system (10% of cases)
  • Carcinoid lung tumor
  • Small cell carcinoma
• Thyroid: medullary carcinoma
• Adrenal glands: pheochromocytoma

Secretory products ^[2]

• Carcinoid tumors can synthesize different hormones (most commonly serotonin).
• Serotonin is degraded via the following mechanisms:
  • First-pass metabolism in the liver
  • Monoamine oxidases in the lung
• Serotonin can reach systemic circulation under the following conditions:
  • Intestinal carcinoid tumors with liver metastases
  • Extraintestinal carcinoid tumors
• ↑ Serotonin in systemic circulation can lead to:
  • Carcinoid syndrome
  • Carcinoid heart disease
  • Pellagra due to increased serotonin metabolism ^[3]

The Measure of thirds for carcinoid tumors: ⅓ are Multiple, ⅓ are associated with another Malignancy, ⅓ Metastasize.

• Carcinoid syndrome
  • Diarrhea and abdominal cramps
  • Cutaneous flushing
    • Caused by vasodilation of small arteries and arterioles
    • Possible triggers: alcohol consumption, food intake, stress
    • In severe cases, may be accompanied by tachycardia and fluctuating blood pressure
  • Dyspnea, wheezing (asthma-like attacks)
  • Palpitations
  • Possible weight loss despite normal appetite
• Carcinoid heart disease ^[4]
  • Endocardial fibrosis that especially affects the right heart
  • Tricuspid insufficiency and/or pulmonary stenosis
  • Symptoms of right-sided heart failure
  • Causes late complications in 20–70% of metastatic carcinoids
• Other symptoms: abdominal pain

In a patient presenting with secretory diarrhea, episodic flushing, wheezing, and cardiac valvular abnormalities, consider a carcinoid tumor.

Approach

• Clinical biochemistry should be performed first if a carcinoid tumor is suspected.
• Imaging tests are then used to localize and stage the tumor.

Clinical biochemistry

• ↑ 5-hydroxyindoleacetic acid (5-HIAA) in 24-hour urine collection
• Fasting plasma 5-HIAA concentration
• Analysis of secretory products (see “Common tumor markers in peripheral blood.”)
  • Chromogranin A
  • NSE
  • Synaptophysin
  • Serotonin
  • Histamine
  • Calcitonin
• ↑ Serotonin serum levels

Imaging

• CT scans of the abdomen and pelvis
• Somatostatin-receptor scintigraphy
• MRI
• Abdominal ultrasound: although not part of the workup, sometimes detects a mass if routinely conducted

Biopsy ^[5]

• Histology: prominent rosettes composed of numerous small monomorphic cells with salt-and-pepper chromatin
• Immunohistochemistry: immunostaining with synaptophysin, chromogranin A, and neuron-specific enolase (NSE) to confirm neuroendocrine origin

Carcinoid lung tumor

• Etiology: association with smoking is not as strong as with lung carcinoma
• Clinical features
  • May be asymptomatic
  • Cough, dyspnea, hemoptysis, recurrent pneumonia
  • Carcinoid syndrome, carcinoid heart disease
• Prognosis: excellent (metastasis is rare)

Ovarian strumal carcinoid ^[6]

• Epidemiology: very rare (0.3–1% of all ovarian tumors)
• Clinical features: usually no symptoms of carcinoid syndrome

Neuroendocrine tumors

Other differential diagnoses

• Angioedema
• Anaphylaxis
• Irritable bowel syndrome
• Celiac disease

The differential diagnoses listed here are not exhaustive.

Operable disease

Surgical resection

• Approach
  • Small intestine: resection of the affected segment and mesentery
  • Appendix: appendectomy
  • Rectum: resection via endoscopy may be possible
  • Liver: ligation of the hepatic artery

Inoperable disease

• Pharmacotherapy
  • Somatostatin analogs (e.g., octreotide) to relieve symptoms
    • ↓ 5-HIAA levels in the urine
    • High-dose treatment slows progression and increases survival time
  • Tryptophan hydroxylase inhibitors (e.g., telotristat) as adjunctive therapy if diarrhea is not controlled with somatostatin analogs
  • Palliative chemotherapy: to reduce rapid tumor progression
• Radiotherapy
  • Radioactively-marked somatostatin analogs
  • Indicated for neuroendocrine tumors expressing somatostatin receptors