Neuroendocrine Tumors of the Gastrointestinal Tract, Lung, and Thymus - Carcinoid Tumors

Carcinoid tumors are rare, slow-growing tumors. Some may be functional neuroendocrine tumors (NETs) of the gastrointestinal system, lungs, or thymus and release hormones or vasoactive substances. These factors cause clinical syndromes characterized by flushing and diarrhea (gastrointestinal) or wheezing and right heart effects (bronchopulmonary). Carcinoid syndromes usually do not occur until tumors metastasize to the liver.

Diagnosis

Indications for Testing

Carcinoid syndrome marked by symptoms of flushing and diarrhea, wheezing, right-sided congestive heart failure

Laboratory Testing

  • Symptoms should guide laboratory testing for biochemical markers (National Comprehensive Cancer Network [NCCN], 2017)
  • Testing for hormones produced by NETs may include
    • 5-hydroxyindoleacetic acid (5-HIAA) (urine or plasma) – for flushing
      • Metabolic product of serotonin
      • Two sequential 24-hour urine samples recommended
      • Significant elevation (10 times the upper reference limit) of urine 5-HIAA may indicate the presence of a carcinoid tumor
    • Chromogranin A
      • Prognostic marker in NETs; elevated levels suggest poorer prognosis (NCCN, 2017)
    • Gastrin – fasting concentrations, with individual off proton-pump inhibitors for 1 week
      • Prognostic marker in gastric tumors with hypergastrinemia syndrome
    • Adrenocorticotropic hormone (ACTH)/cortisol – useful in thymic and bronchial tumors with Cushing syndrome
    • Serotonin – whole blood preferred over serum
      • Highly specific for carcinoid identification
      • Not frequently used
    • Neurokinin A – prognostic marker for midgut NETs

Histology

  • Definitive diagnosis requires biopsy and pathologist examination
  • Useful immunohistochemical stains may include chromogranin A, synaptophysin, and cytokeratin 8,18
  • For detailed descriptions, refer to ARUP’s Immunohistochemistry Stain Offerings

Imaging Studies

  • Computed tomography (CT)/magnetic resonance imaging (MRI)
    • Abdomen and pelvis
  • Echocardiography
    • For bronchopulmonary effects
    • Evaluate valvular thickening and leaflet damage
  • Endoscopy
    • As indicated by location (esophagogastroduodenoscopy [EGD], colonoscopy)
  • Other imaging as indicated
    • Bronchoscopy
    • CT of chest
    • CT enterography or capsule endoscopy
    • Endorectal MRI
    • Endoscopic ultrasound
    • Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT and brain imaging with CT/MRI for poorly differentiated carcinomas
    • MRI with gadoxetate
    • Somatostatin receptor-based imaging

Differential Diagnosis

Monitoring

  • Postresection surveillance based on tumor type and location (NCCN, 2017) 
    • Small bowel/colon, rectal, thymus carcinoids
      • Reevaluate 3-12 months after resection
        • Consider 5-HIAA, chromogranin A testing
          • Normal 5-HIAA does not rule out tumor recurrence
        • CT or MRI
      • Reevaluate every 6-12 months for up to 10 years
        • Consider 5-HIAA, chromogranin A testing
        • Imaging as clinically indicated
    • Gastric carcinoids
      • Type 1 or 2 gastric NETs with increased gastrin
        • Marker levels and EGD
          • Every 6-12 months during years 1-3; annually thereafter
          • Gastrin levels usually uninformative in type 1 tumors 
        • Imaging as clinically indicated
      • Type 3 gastric NETs with normal gastrin
        • Reevaluate 3-12 months after resection
          • Consider chromogranin A testing
          • CT or MRI
        • Reevaluate every 6-12 months for up to 10 years
          • Consider chromogranin A testing
          • Imaging as clinically indicated
    • Bronchial carcinoids – see recommendations for non-small cell lung cancer (NSCLC)
      • Chest x-ray, CBC, and chemistries every 3-6 months for first 2 years
        • CT recommended every 6 months for 2-3 years in NSCLC
      • Echocardiogram – every 2-3 years

Background

Epidemiology

  • Incidence
    • 5/100,000 in U.S. (all NETs) (NCCN, 2017)
  • Age – bimodal peaks
    • 15-25 years
    • 65-75 years
  • Sex – distribution inverts at 50 years
    • <50 years, M<F, 1:2
    • ≥50 years, M>F, 2:1
  • Occurrence – most frequently sporadic
  • Ethnicity – somewhat higher incidence in African Americans

Risk Factors

  • 15-20% of NETs are related to genetic syndromes 
    • Multiple endocrine neoplasia type 1 (MEN1) – neoplasia of the parathyroid, pancreas, or anterior pituitary with 10% incidence of NETs of the lung, thymus, and stomach
    • von Hippel-Lindau syndrome – pancreatic neoplasia of neuroendocrine origin occurs in ~15% of cases
    • Neurofibromatosis type 1 (von Recklinghausen disease) – infrequent carcinoids of the duodenum
    • Tuberous sclerosis

Pathophysiology

  • Tumor derived from enterochromaffin cells (Kulchitsky cells)
  • May secrete various hormones, vasoactive substances
    • Bronchial/thymic – ACTH
    • Small intestine/appendix – serotonin, histamine, tachykinins
  • Gastrointestinal (GI) tumors – classified by tumor location
    • Foregut – pancreas, duodenum, bronchus, thymus, stomach
    • Midgut – jejunum, ileum, ascending colon, appendix
    • Hindgut – transverse and descending colon, rectum

Clinical Presentation

  • Relatively slow-growing tumor with nonspecific presentation
    • May be found coincidentally during surgery for appendicitis or bowel obstruction
  • Classic carcinoid syndrome – occurs in ~10% of patients
    • Usually occurs with liver metastases; rarely occurs with lung tumors
      • May also produce ACTH
    • Symptoms include
      • Flushing, wheezing, diarrhea
      • Carcinoid heart disease – congestive heart failure, cardiac murmurs, jugular venous distension
        • Predominantly involves the right-side heart valves (tricuspid, pulmonic) – fibrosis, thickening of valves
        • Develops in 45-60% of patients with metastatic disease as late complication
      • May be precipitated by certain foods or drinks high in tyramine (eg, blue cheese, chocolate, red wine)
  • Gastrointestinal manifestations
    • Diarrhea
    • Abdominal pain (often secondary to fibrosis)
    • Gastric carcinoids
      • Type 1 associated with chronic atrophic gastritis – absent acid secretion and hypergastrinemia
      • Type 2 associated with Zollinger-Ellison syndrome, hypergastrinemia, and MEN1
      • Type 3 sporadic – normal gastrin levels
  • Metastatic disease – tumors <1 cm rarely metastasize

ARUP Laboratory Tests

Primary Tests

Diagnose carcinoid tumors

Monitor disease

Increased urine 5-HIAA concentration is common and may be the result of improper specimen collection, consumption of serotonin containing foods or dietary supplements, drug interference, or malabsorption syndromes

Serotonin must be avoided 72 hours before and during collection of urine specimen

Diagnose carcinoid tumors and monitor disease

Acceptable alternative to 5-HIAA urine

Monitor carcinoid tumors; not recommended for diagnosis

Monitor nonsecretory sympathetic and parasympathetic NETs

Results obtained with different assay methods or kits cannot be used interchangeably

Diagnose carcinoid and gastrinoma tumors

12-hour fast prior to collection is recommended

Diagnose and monitor carcinoid tumors

Preferred serotonin test since most of the blood serotonin resides in the platelets

Certain medications may affect serotonin

Foods containing serotonin do not significantly interfere

Slight increases may be seen in acute intestinal obstruction, acute myocardial infarction, cystic fibrosis, dumping syndromes and nontropical sprue

Assist in prognosis of patients with midgut NETs

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Not recommended for diagnosis of carcinoid tumors

May be useful in correlation with clinical symptoms of functioning carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Not recommended for histological diagnosis

Useful in determining grade and as a possible prognostic marker in carcinoid tumors of the gastroenteropancreatic tract

Not currently recommended for determining grade or prognosis in carcinoid tumors of the lung; may be performed and simply reported as a proliferation index

Stained and returned to client pathologist for interpretation; consultation available if needed

For test with interpretation order Ki-67 with interpretation by IHC

Aid in determining tumor grade and prognosis of gastroenteropancreatic tract carcinoid tumors

May be performed in lung NETs and reported to clinicians but not currently recommended for use in diagnosis, grade, or prognosis of these tumors

Stained and resulted by ARUP

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

Related Tests

Use as a tumor marker for evaluation of NETs

Screen for thymic and bronchial carcinoid tumors

Aid in diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

Preferred serotonin specimen when diagnosing carcinoid tumors is whole blood

Medical Experts

Contributor

Frank

Elizabeth L. Frank, PhD, DABCC
Professor of Clinical Pathology, University of Utah
Medical Director, Analytic Biochemistry, Calculi and Manual Chemistry; Co-Medical Director, Mass Spectrometry, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®