Neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) are tumors derived from neuroendocrine cells that can produce amines and/or peptide hormones. Well-differentiated epithelial NENs are classified as neuroendocrine tumors (NETs), which typically grow slowly but may metastasize. NETs predominantly arise from the GI tract and the lungs. Poorly differentiated epithelial NENs are classified as neuroendocrine carcinomas (NECs), which are all high-grade and subclassified by cell type (i.e., large or small). NETs and NECs can occur in endocrine and nonendocrine organs throughout the body. NENs originating from neural structures are classified as paragangliomas.

Most NETs are sporadic, but a positive family history, especially of genetic syndromes such as MEN 1, increases the risk. Some NENs cause paraneoplastic syndromes (e.g., carcinoid syndrome, Zollinger-Ellison syndrome) due to excess bioactive amines or peptide hormones (e.g., serotonin, insulin, gastrin). Levels of these hormones and nonspecific neuroendocrine markers (e.g., chromogranin A) are measured to support the diagnosis. Surgical resection is indicated for localized disease and, in some cases, metastatic disease to alleviate pain and/or reduce hormone production. Systemic therapy (e.g., octreotide) can mitigate the hormonal effects of unresectable metastatic disease.

• Neuroendocrine neoplasm (NEN): an umbrella term for a heterogeneous group of tumors derived from neuroendocrine cells that share common features (e.g., secretory granules, hormone production)
• Functioning NENs: produce and secrete bioactive substances and are associated with paraneoplastic syndromes (e.g., carcinoid syndrome)
• Nonfunctioning NENs: produce but do not secrete bioactive substances at clinically significant levels
• Carcinoid tumor: historically used interchangeably with “neuroendocrine neoplasm” or to refer to gastrointestinal NETs; currently only used specifically for carcinoid lung tumors and ovarian carcinoid tumors ^[3]

Neuroendocrine cells (e.g., pancreatic β-cells, enterochromaffin cells) belong to the APUD cell series and share a common biological function, despite their different embryologic origins, anatomical sites, and secretory products (e.g., serotonin, histamine). ^[4]

Classification ^[2]

The terminology for NENs varies across the literature. The following reflects the 2022 WHO taxonomy. ^[2]

• Neuroendocrine tumors (NETs): well-differentiated epithelial NENs with malignant potential
  • Subtypes vary by tumor location
  • Tumor grade (G1-G3) is based on histopathology
• Neuroendocrine carcinomas (NECs): poorly differentiated malignant epithelial NENs
  • Subtyped as either large cell or small cell
  • High tumor grade by definition
• Paragangliomas: NENs arising from neural crest cells in the autonomic ganglia or adrenal medulla

Tumor locations ^[2][5]

• NETs: endocrine and nonendocrine organs throughout the body
  • GI tract, including the pancreas (62–67%) ^[5]
    • Gastric, small intestine, colorectal, and appendiceal NETs
    • Pancreatic NETs, e.g.:
      • Insulinoma
      • Glucagonoma
      • Gastrinoma
      • VIPoma
      • Somatostatinoma
  • Bronchopulmonary system (22–27%), e.g., lung NET ^[5]
  • Other organs (rare), e.g., ovarian carcinoid
• NECs: endocrine and nonendocrine organs throughout the body
  • Small cell lung cancer
  • Large cell NEC (e.g., of the lung, thymus)
  • Medullary thyroid cancer
  • Merkel cell carcinoma
  • Other NECs, e.g., gastrointestinal, esophageal, and cervical NECs
• Paragangliomas: : most commonly in the adrenals (i.e., pheochromocytoma)

Associated genetic syndromes ^[1]

Genetic syndromes associated with an increased risk of NENs include:

• MEN type 1 (e.g., pancreatic, gastric, duodenal, thymic, bronchial NENs)
• Von Hippel-Lindau syndrome (pancreatic NENs)
• Neurofibromatosis type 1 (somatostatinomas)

The Measure of thirds for NETs: one-third are Multiple, one-third are associated with another Malignancy, and one-third Metastasize.

Clinical features vary widely based on mass size, location, and endocrine activity. ^[1]

• Asymptomatic: e.g., with nonfunctioning incidentalomas
• Endocrine activity (in functioning tumors, including tumors of unknown origin), e.g.:
  • Carcinoid syndrome
  • Zollinger-Ellison syndrome
  • Clinical features of somatostatinoma (e.g., glucose intolerance, cholelithiasis, steatorrhea)
• Mass effect, e.g.:
  • Pain (e.g., abdominal pain)
  • Change in bowel habits or clinical features of bowel obstruction (rare)
  • Symptoms of local compression (e.g., airway compression in lung NENs)

Biopsy ^[6]

Biopsy is typically performed to confirm the diagnosis and obtain tissue for further characterization (e.g., grading, receptor status).

• Histopathology: nests of cells with round or oval nuclei with “salt-and-pepper” chromatin
• Immunohistochemistry: immunostaining for synaptophysin, chromogranin A, and neuron-specific enolase to confirm neuroendocrine origin
• Grading
  • All NECs are high-grade (G3)
  • NET grading is based on the Ki-67 index and/or mitotic rate (whichever is higher) as determined by a pathologist
    • G1: low-grade, consistent with indolent growth
    • G2: intermediate-grade, variable growth (can be aggressive)
    • G3: high-grade, aggressive growth

Laboratory studies ^[7]

• Analyze secretory products (nonspecific) in consultation with a specialist to support the diagnosis or monitor treatment response.
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • Serotonin
  • Histamine
  • Calcitonin
  • See also “Common tumor markers in peripheral blood.”
• Diagnostics for carcinoid syndrome (e.g., 24-hour urinary excretion of 5-hydroxyindoleacetic acid)
• Targeted testing for suspected paraneoplastic syndromes (e.g., fasting serum gastrin and gastric pH for gastrinomas)

Imaging ^[8][9][10]

• Cross-sectional imaging
  • Modalities: CT with contrast, MRI
  • Uses: location and assessment of primary and metastatic NENs
• Somatostatin-receptor imaging
  • Modalities: PET/CT (preferred), scintigraphy
  • Uses: whole-body staging, detection of small tumors and metastases
• Conventional imaging (not standard for NEN workup)
  • Modalities: ultrasound, chest x-ray
  • Uses: may detect a mass when performed for another indication (low sensitivity)

Approx. 27% of patients with NETs have distant metastasis at diagnosis. ^[5]

Treatment is based on the grade and stage of the tumor and should be guided by appropriate specialists (e.g., oncology, gastroenterology). ^[8][11]

• Expectant management
  • Consider for patients without a paraneoplastic syndrome, including those with small, indolent metastases.
  • Monitor NETs with imaging (e.g., for midgut NETs, every 3–4 months initially, then every 6 months). ^[12]
• Surgical resection
  • For localized disease
  • For metastatic disease to alleviate pain and/or reduce hormone production
• Systemic therapy, e.g.:
  • Somatostatin analogues (e.g., octreotide) for treatment of carcinoid syndrome
  • Palliative chemotherapy to slow tumor progression
  • Radiolabeled somatostatin analogues for NETs expressing somatostatin receptors
• Additional interventional therapies on a case-by-case basis, e.g.:
  • Hepatic arterial embolization
  • Radiofrequency ablation
  • Surgical debulking