What are neuroendocrine tumors of the bowel?

Neuroendocrine Tumors of the Bowel

Neuroendocrine tumors (NETs) of the bowel are a heterogeneous group of neoplasms that originate from neuroendocrine cells of the embryological gut, characterized by their ability to secrete hormones and express specific neuroendocrine markers. 1

Definition and Origin

• NETs arise from pluripotential progenitor cells that develop neuroendocrine characteristics in the digestive system 1
• They originate from diffuse neuroendocrine cells distributed throughout the gut, not from neural crest migration as previously thought 1
• These tumors share common histochemical features, including immunoreactivity for "pan-neuroendocrine" markers such as chromogranin A and synaptophysin 1, 2

Classification

By Differentiation and Grade

• WHO Classification (2010) 1:
  • WHO 1: NET G1 (Ki-67 ≤2%) - Well-differentiated, low-grade
  • WHO 2: NET G2 (Ki-67 3%-20%) - Well-differentiated, intermediate-grade
  • WHO 3: NEC G3 (Ki-67 >20%) - Poorly differentiated, high-grade
  • MANEC: Mixed adenocarcinoma and neuroendocrine carcinoma
  • Tumor-like lesions

By Location

• Intestinal NETs (about two-thirds of GEP-NETs) 1:
  • With carcinoid syndrome (30% of carcinoids)
  • Without carcinoid syndrome (70% of carcinoids)
• Pancreatic NETs (about one-third of GEP-NETs) 1:
  • Non-functioning (45%-60%)
  • Functioning (40%-55%)

By Embryological Origin

• Foregut: Bronchi, stomach, pancreas, gallbladder, duodenum
• Midgut: Jejunum, ileum, appendix, right colon
• Hindgut: Left colon, rectum 1

Epidemiology

• Incidence has significantly increased over recent years, from 3.0 to 5.25 cases per 100,000 per year 1
• Prevalence estimated at 35 per 100,000 per year 1
• Most common sites in the digestive system 1, 2:
  • Small intestine (0.95/100,000/year)
  • Rectum (0.86/100,000/year)
  • Pancreas (0.32/100,000/year)
  • Stomach (0.30/100,000/year)
• Slight male predominance (5.35 vs 4.76 in females) 1
• Most common age: fifth decade onwards, except appendiceal NETs which peak at age 40 1
• In the US, NETs have increased by 300%-500% in the last 35 years 3

Pathophysiology and Molecular Features

• NETs express specific markers that help identify them 2:
  • Chromogranin A
  • Synaptophysin
  • Neuron-specific enolase (NSE)
  • CD56
• Small intestinal and pancreatic NETs have different molecular signatures 1
• Most NETs are sporadic, but some are associated with genetic syndromes 1:
  • Multiple endocrine neoplasia type 1 (MEN1) - 5% of cases
  • Von Hippel-Lindau (VHL) disease
  • Tuberous sclerosis (TSC)
  • Neurofibromatosis

Clinical Presentation

• Many NETs are asymptomatic and discovered incidentally during screening examinations 4
• Carcinoid syndrome occurs in 30% of intestinal NETs, characterized by 1:
  • Flushing
  • Diarrhea
  • Endocardial fibrosis
  • Wheezing
  • Caused by serotonin release predominantly from liver metastases

Diagnosis

Histopathology

• Tissue samples obtained via endoscopic biopsy, surgery, or core needle biopsy 1
• Key features include:
  • Immunoreactivity for chromogranin A and synaptophysin 1
  • Proliferation potential evaluated by Ki-67 (MIB-1) staining 1
  • Mitotic count assessment 2

Biochemical Markers

• Chromogranin A in plasma - general tumor marker for all NETs 1
• Specific markers based on clinical symptoms 1:
  • Urinary 5-HIAA for carcinoid syndrome
  • Gastrin for Zollinger-Ellison syndrome
  • Insulin/pro-insulin for hypoglycemic syndrome
  • NSE for poorly differentiated G3 tumors

Imaging

• Somatostatin receptor scintigraphy (SRS) - primary method for staging 1
• CT or MRI depending on tumor location 1
• PET scanning with specific tracers (11C-5HTP, 18F-DOPA, 18F-DG) 1
• Endoscopy (gastroscopy, endoscopic ultrasonography, colonoscopy) 1

Prognosis and Mortality

• Prognosis varies significantly based on:
  • Tumor grade and differentiation 2
  • Primary site 2
  • Disease stage 2
  • Ki-67 index 2
• 5-year survival for midgut carcinoid tumors is approximately 60% for all stages 1
• Grade 3 NECs have significantly worse outcomes compared to G1-G2 NETs 2
• For small bowel NETs with modern multimodal treatment, overall survival at 5 and 10 years can reach 91.0% and 82.5%, respectively 5

Management Considerations

• Treatment approach depends on tumor location, size, and differentiation 3
• Small duodenal NETs (<10mm, limited to mucosa/submucosa): Endoscopic resection 3
• Duodenal NETs 10-20mm: Require interdisciplinary discussion 3
• Duodenal NETs >20mm: Surgical resection 3
• Ileal NETs: Surgical resection recommended for all 3
• Advanced ileal NETs with carcinoid syndrome: Long-acting somatostatin analogs 3
• Poorly differentiated NECs: Typically treated with platinum-based combination chemotherapy 2

Key Pitfalls to Avoid

• Terminology confusion: The term "carcinoid" should be limited to well-differentiated midgut NETs that secrete serotonin, not used for all neuroendocrine neoplasms 2
• Delayed diagnosis: Due to nonspecific clinical manifestations, NETs are often not readily considered in differential diagnosis 6
• Underestimating metastatic potential: Most small bowel NETs present in a metastasized stage despite slow growth 5
• Missing hereditary syndromes: Always consider genetic syndromes (MEN1, VHL) in younger patients with NETs 1

NETs of the bowel represent a complex and heterogeneous group of tumors requiring specialized expertise for optimal management. Early detection and appropriate classification are crucial for determining the best treatment approach and improving patient outcomes.