Neuroendocrine tumor (NET)

A neuroendocrine tumor (NET) is a type of tumor that originates from neuroendocrine cells.

These cells have both neural and hormonal properties and are found throughout the body—primarily in the gastrointestinal tract, pancreas, and lungs.

What characterizes neuroendocrine tumors?

  • They often produce hormones (e.g., serotonin, insulin), which can lead to hormonal syndromes.
  • They can be benign or malignant.
  • They usually grow slowly but can metastasize (e.g., to the liver or lymph nodes).
  • They are often discovered incidentally, e.g., during imaging procedures.

List of key neuroendocrine tumors by location

Gastroenteropancreatic NETs (GEP-NETs)
These represent the majority of NETs:

  • Carcinoid tumors (small intestine, appendix)
  • Gastrinoma (stomach, pancreas) – produces gastrin
  • Insulinoma (pancreas) – produces insulin
  • Glucagonoma (pancreas) – produces glucagon
  • VIPoma (pancreas) – produces vasoactive intestinal peptide
  • Somatostatinoma (pancreas/small intestine) – produces somatostatin
  • Non-functional NETs (e.g., in the pancreas) – do not produce hormones

 Pulmonary NETs (lungs)

  • Typical carcinoid
  • Atypical carcinoid
  • Small cell lung cancer (SCLC) – very aggressive
  • Large cell neuroendocrine carcinoma (LCNEC) – also high-grade

 Other NETs

  • Merkel cell carcinoma – skin, very aggressive
  • Paraganglioma – outside the adrenal glands, mostly in the head/neck area
  • Pheochromocytoma – adrenal medulla, produces catecholamines
  • Medullary thyroid carcinoma – produces calcitonin
  • Pituitary tumors (e.g., prolactinoma, ACTH-producing)

 Diagnostics

  • Blood and urine tests: e.g., Chromogranin A, 5-HIAA
  • Imaging: CT, MRI, PET-CT with somatostatin receptor ligands
  • Histology: Ki-67 index for grading (G1–G3)

Classification (WHO)

  • NET G1: well-differentiated, slow-growing
  • NET G2: moderately differentiated
  • NEC (neuroendocrine carcinoma) G3: poorly differentiated, fast-growing

Treatment of neuroendocrine tumors (NETs) depends on their origin, differentiation (well or poorly differentiated), functionality (hormone-producing or not), and stage (localized or metastatic). Treatment is often multimodal. Here’s an overview of key treatment options:

  1. Surgical Therapy
  • Curative resection: Full surgical removal of the tumor is the preferred therapy if feasible.
  • Debulking: In metastatic NETs, large portions of the tumor may be removed to reduce symptoms or improve the effectiveness of other treatments.
  1. Medical Therapy
  2. a) Somatostatin analogues (SSA)
  • e.g., Octreotide, Lanreotide
  • Inhibit hormone production in functional NETs (e.g., carcinoid syndrome) and have tumor growth-inhibiting effects.
  • Often used for long-term therapy.
  1. b) Targeted Therapy
  • Everolimus (mTOR inhibitor): for NETs of the lung or pancreas
  • Sunitinib (tyrosine kinase inhibitor): especially for pancreatic NETs
  1. c) Chemotherapy
  • Mostly for poorly differentiated, more aggressive NETs (e.g., neuroendocrine carcinomas – NEC)
  • Common regimens: e.g., Streptozotocin + 5-FU or Temozolomide + Capecitabine
  1. Peptide Receptor Radionuclide Therapy (PRRT)
  • For NETs with high somatostatin receptor expression
  • e.g., Lutetium-177-DOTATATE
  • Radioactive substance binds specifically to tumor cells → internal radiation therapy
  1. Supportive Therapy
  • Treatment of hormone-related symptoms (e.g., with SSA or Interferon-α)
  • Antidiarrheals, antiemetics, heart medications in carcinoid heart disease
  1. Local Ablative Procedures
  • e.g., radiofrequency ablation or embolization for liver metastases
  1. Watch and Wait
  • For slowly growing, asymptomatic tumors, active monitoring may be sufficient initially

Interdisciplinary Approach

Treatment should be planned at a specialized tumor center by an interdisciplinary team (oncology, endocrinology, surgery, nuclear medicine, radiology).

Decision Matrix for NET Therapy

(Depending on tumor characteristics and stage. It provides a general overview and is not a substitute for personalized treatment planning by an interdisciplinary tumor board.)

Criterion

Therapy Option(s)

Notes

Differentiation: well-differentiated (G1/G2)

– Surgery (if resectable) – SSA – PRRT (if SSTR-positive)

SSA for hormone control and tumor growth inhibition

Differentiation: poorly differentiated (NEC, G3)

– Chemotherapy (e.g., Cisplatin + Etoposide) – Possibly radiotherapy

Aggressive course → primarily systemic treatment

Primary tumor: Pancreas (pNET)

– Surgery (if possible) – SSA – Targeted Therapy (Everolimus, Sunitinib) – PRRT

pNETs often non-functional, respond well to targeted therapies

Primary tumor: Small intestine / Stomach (GI-NET)

– SSA (if functional tumor) – PRRT – Surgery (also consider for liver mets)

Hormonal control is key (e.g., in carcinoid syndrome)

Hormonally active (functional)

– SSA – Possibly Interferon-α – Symptom management (e.g., antidiarrheals, cardiac therapy)

Symptom control is a priority

Metastasis: Liver metastases

– PRRT (if SSTR+) – SSA – Liver embolization/ablation – Possibly surgery

Multimodal therapy often beneficial

Non-resectable tumor

– SSA – PRRT – Targeted Therapy – Possibly “watchful waiting” (if indolent)

Treatment depends on growth dynamics and symptoms

SSTR-negative

– Chemotherapy (for aggressive tumors) – Targeted Therapy (pNET)

PRRT only effective in SSTR-positive tumors

Legend:
• SSA = Somatostatin analogues
• PRRT = Peptide Receptor Radionuclide Therapy
• SSTR = Somatostatin receptor
• pNET = Pancreatic neuroendocrine tumor
• NEC = Neuroendocrine carcinoma (high-grade malignancy)