What is the role of the lung in the neuroendocrine system?

The Role of the Lung in the Neuroendocrine System

The lung plays a crucial role in the neuroendocrine system through pulmonary neuroendocrine cells (PNECs) that function as oxygen sensors, regulate airway growth and development, and can give rise to neuroendocrine tumors. 1, 2

Pulmonary Neuroendocrine Cells (PNECs)

Structure and Distribution

• PNECs exist as either solitary cells or clustered aggregates called neuroepithelial bodies (NEBs) within the ciliated epithelium of airways 1
• Approximately 70% of these cells are located in the major bronchi, with the remainder in the peripheral lung tissue 1
• They occur more frequently (60-61%) in the right lung than in the left lung, particularly in the middle lobe 1

Cellular Characteristics

• PNECs express specific neuroendocrine markers:
  • Serotonin
  • Neuron-specific enolase (NSE)
  • Gastrin-releasing peptide (GRP)
  • Chromogranin A
  • Synaptophysin 1, 3

Physiological Functions

Oxygen Sensing and Respiratory Regulation

• PNECs function as oxygen-sensitive chemoreceptors that respond to hypoxia 2
• During hypoxic conditions, PNECs secrete serotonin, inducing local vasoconstriction to:
  • Decrease blood flow in poorly ventilated areas of the lung
  • Redirect blood toward better ventilated areas 1
• This mechanism helps optimize ventilation-perfusion matching in the lungs

Developmental and Growth Regulation

• PNECs are the first specialized cell type to appear in the developing lung 4
• They stimulate airway epithelial cell differentiation and regulate lung development 2, 5
• PNECs are most numerous during fetal and neonatal periods, suggesting their importance in early lung development 5

Stem Cell Properties

• Recent research has revealed that rare PNECs (typically 2-4 per cluster) function as stem cells 6
• These cells can:
  • Self-renew following injury
  • Migrate into injured areas
  • Lose their neuroendocrine identity (deprogram)
  • Differentiate into other cell types (reprogram) 6, 4
• Following lung injury, PNECs can contribute to Clara cells and ciliated cells as part of the repair process 4

Neuroendocrine Tumors of the Lung

Classification and Epidemiology

• Pulmonary neuroendocrine tumors comprise about 25% of all NETs and 20-25% of all invasive lung malignancies 1, 3
• They are classified into four main types:
  1. Typical carcinoid (TC) - low-grade, <2 mitoses/10 HPF
  2. Atypical carcinoid (AC) - intermediate-grade, 2-10 mitoses/10 HPF
  3. Large cell neuroendocrine carcinoma (LCNEC) - high-grade, >10 mitoses/10 HPF
  4. Small cell lung cancer (SCLC) - high-grade, >80 mitoses/10 HPF 1
• The annual incidence of lung neuroendocrine tumors is approximately 1.35-1.57/100,000 population 1

Hormonal Syndromes

• Pulmonary NETs can produce various hormones and peptides, leading to paraneoplastic syndromes:
  • Cushing's syndrome due to ectopic ACTH production (in approximately 2% of cases) 1
  • Carcinoid syndrome (rare in bronchial NETs, <2% of cases) 1
• Carcinoid crisis may occur in previously asymptomatic patients following procedures such as bronchoscopic biopsy, surgical manipulation, or peptide receptor radiotherapy 1

Genetic Considerations

• Bronchial NETs may be part of multiple endocrine neoplasia type 1 syndrome (MEN-1) in 5-15% of cases 1
• SCLC tumor suppressors (Rb and p53) regulate PNEC stem cell self-renewal 6
• Notch signaling is involved in marking stem cells and initiating deprogramming and transit amplification 6

Clinical Implications

Diagnosis and Evaluation

• Symptoms of central bronchial NETs include hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort, and unilateral wheezing 1
• Peripheral carcinoids are often asymptomatic and discovered incidentally 1
• Diagnostic workup includes:
  • Chest X-ray and CT scan
  • Bronchoscopy
  • Somatostatin receptor scintigraphy (particularly in cases with ectopic hormone production)
  • PET scan (may be false-negative in low-grade tumors) 1

Prognostic Factors

• Histologic grade is the dominant driver of prognosis in pulmonary neuroendocrine tumors 7
• Current staging systems should incorporate histologic grade with traditional TNM parameters for better prognostic discrimination 7

Pathological Considerations

• Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare preneoplastic condition comprising generalized proliferation of PNECs, predominantly in women and non-smokers 1
• PNECs are proposed to be the cells of origin for small cell lung cancer 6, 4

Understanding the role of PNECs in the neuroendocrine system has significant implications for comprehending lung development, response to injury, and the pathogenesis of neuroendocrine tumors.