Neuroendocrine Neoplasms (NENs): A Comprehensive Overview

I. Definition and Classification

Neuroendocrine neoplasms (NENs) are heterogeneous tumors arising from peptidergic neurons and neuroendocrine cells, characterized by neuroendocrine differentiation and hormone or bioactive peptide secretion. According to the 2022 WHO classification, NENs are categorized into:

• Well-differentiated neuroendocrine tumors (NETs): Slow-growing, functional tumors (e.g., typical carcinoids like pulmonary carcinoids, atypical carcinoids).
• Poorly differentiated neuroendocrine carcinomas (NECs): Aggressive, poorly differentiated tumors (e.g., small-cell carcinoma, large-cell neuroendocrine carcinoma).
• Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN): Contain both neuroendocrine and non-neuroendocrine components.

Functional Classification:

• Functional NENs (~20%): Secrete hormones causing clinical syndromes (e.g., insulinoma, gastrinoma, carcinoid syndrome).
• Non-functional NENs (~80%): Asymptomatic until mass effects or metastasis occur.

Genetic Associations:

• Approximately 5%–10% of NENs are linked to hereditary syndromes (e.g., multiple endocrine neoplasia types 1/2/4, von Hippel-Lindau syndrome, neurofibromatosis type 1).

II. Epidemiology and Clinical Features

• Incidence:
  • Globally rising, with U.S. annual incidence ~6.98 per 100,000.
  • Most common primary sites: Gastroenteropancreatic system (GEP-NENs, 65%–75%), followed by lungs and thymus.
• Age and Sex:
  • Peak occurrence: 50–60 years; sex varies by site (e.g., pancreatic NENs favor males, genitourinary NENs females).
• Clinical Presentation:
  • Functional NENs: Hormone-driven symptoms (e.g., hypoglycemia in insulinoma, Zollinger-Ellison syndrome in gastrinoma).
  • Non-functional NENs: Abdominal pain, weight loss, palpable masses, or metastatic symptoms (e.g., liver metastases).

III. Diagnosis and Evaluation

Laboratory Testing

• General Biomarkers: Chromogranin A (CgA), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP).
• Functional Hormone Assays: Insulin, gastrin, serotonin.
• Liquid Biopsy: Circulating transcriptome-based NETest (sensitivity 97%, specificity 93%).

Imaging

• Conventional: CT/MRI for localization and staging.
• Molecular Imaging:
  • 68Ga-SSA PET-CT: Detects somatostatin receptor expression for PRRT eligibility.
  • 18F-FDG PET-CT: Evaluates high-proliferative tumors (e.g., G3 NECs).

Pathology

• Grading:
  • G1 (Ki-67 ≤3%), G2 (Ki-67 3%–20%), G3 (Ki-67 >20%).
• Immunohistochemistry: Synaptophysin, chromogranin A, CD55.

IV. Molecular Pathology and Tumor Microenvironment

• Genetic Features:
  • NETs: MEN1, ATRX, DAXX mutations (pancreatic NETs); chromosome 18 deletions (small intestinal NETs).
  • NECs: TP53 and RB1 mutations, molecular overlap with small-cell lung cancer (SCLC).
• Tumor Microenvironment:
  • Immune Infiltration: CD8+ T cells and NK cell activity correlate with better prognosis; PD-L1 expression suggests immunotherapy potential.
  • Tertiary Lymphoid Structures (TLS): Presence in non-functional pancreatic NETs improves prognosis.

V. Treatment Strategies

Surgery

• Localized Tumors: Curative resection (e.g., enucleation for pancreatic NETs ≤2 cm).
• Liver Metastases: Hepatectomy, radiofrequency ablation, or transplantation (select cases).

Medical Therapy

• Somatostatin Analogs (SSAs): Control hormonal symptoms and slow progression (e.g., octreotide, lanreotide).
• Targeted Therapy: Everolimus (mTOR inhibitor), sunitinib (anti-angiogenic) for advanced pancreatic NETs.
• Chemotherapy: Platinum-based regimens (e.g., cisplatin + etoposide) for G3 NECs.

Radionuclide Therapy

• Peptide Receptor Radionuclide Therapy (PRRT): 177Lu-DOTATATE for SSTR-positive tumors (median PFS: 28.4 months).

Hepatic Artery Interventions

• Transarterial embolization (TAE) or chemoembolization (TACE) for liver metastasis debulking.

VI. Prognosis and Survival

• Prognostic Factors:
  • Grade and Stage: G1 NETs have >95% 5-year survival; G3 NECs median survival <12 months.
  • Metastasis: Localized disease outperforms metastatic (e.g., pancreatic NETs with liver metastases: 5-year survival ~30%).
• Heterogeneity: NETs may transform into NECs, requiring dynamic monitoring (e.g., Ki-67 index changes).

VII. Future Directions

• Precision Medicine:
  • Multi-omics molecular subtyping (e.g., transcriptomic profiles) for tailored therapies.
  • Targeted drugs for MEN1 and ATRX mutations.
• Liquid Biopsy: NETest combined with ctDNA for early relapse detection.
• Interdisciplinary Integration:
  • AI-driven prognostic models, CAR-T therapy, and novel PRRT isotopes (e.g., 225Ac-labeled SSAs).

Conclusion

NENs are highly heterogeneous, requiring integrated pathological, molecular, and clinical evaluation. Advances in multi-omics, liquid biopsy, and targeted therapies are driving personalized management. Future efforts must address tumor heterogeneity, treatment resistance, and interdisciplinary collaboration.

Data sourced from public references. Contact: chuanchuan810@gmail.com.