Neuroendocrine Neoplasms (NENs)

Introduction

Intestinal NENs arise from enterochromaffin cells (Kulchitsky cells) located at the base of the crypts of Lieberkühn.
Also known as argentaffin cells due to their staining by silver compounds.
First described by Lubarsch in 1888; the term "carcinoid" was coined by Oberndorfer in 1907.
- Initially thought to lack malignant potential, but now recognized that all NENs have malignant potential.
Commonly found in organs like the lungs, bronchi, and the gastrointestinal tract.

Classification

Based on tumor grade and differentiation:
- Neuroendocrine Tumors (NETs): Well-differentiated, can be benign or malignant.
  - Subdivided into:
    - Grade 1 (G1): Low-grade.
    - Grade 2 (G2): Intermediate-grade.
    - Grade 3 (G3): High-grade.
  - Classification considers appearance, mitotic rates, behavior (e.g., invasion), and Ki-67 proliferative index.
- Neuroendocrine Carcinomas (NECs): Poorly differentiated, all are G3.
Categorization by Embryologic Origin:
- Foregut NETs: Respiratory tract, thymus; produce low levels of serotonin, may secrete 5-hydroxytryptophan or adrenocorticotropic hormone.
- Midgut NETs: Jejunum, ileum, right colon, stomach, proximal duodenum; characterized by high serotonin production.
- Hindgut NETs: Distal colon, rectum; rarely produce serotonin but may produce somatostatin and peptide YY.

Pathology

Common Sites:
- Small intestine is a frequent site after the appendix.
- Typically occur within the last 2 feet of the ileum.
Gross Appearance:
- Small, firm, submucosal nodules, often yellow on cut surface.
- May appear as small whitish plaques on the antimesenteric border.
Malignant Potential:
- Size Correlation:
  - <1 cm: Metastasis in ~2% of cases.
  - 1–2 cm: Metastasis in 50% of cases.
  - 2 cm: Metastasis in 80–90% of cases.
- Location Impact:
  - ~3% of appendiceal NETs metastasize.
  - ~35% of ileal NETs are associated with metastasis.
Multicentricity:
- Occur in 20–30% of patients, more than any other gastrointestinal malignancy.
Associated Conditions:
- Multiple Endocrine Neoplasia Type 1 (MEN1) is associated in ~10% of cases.
- Coexistence with a second primary malignant neoplasm (often synchronous adenocarcinoma) occurs in 10–20% of patients.

Clinical Manifestations

General Symptoms:
- Often asymptomatic; 70–80% found incidentally during surgery.
- Abdominal pain is the most common symptom.
- Symptoms of partial or complete intestinal obstruction.
- Diarrhea and weight loss may occur.
Carcinoid Syndrome:
- Occurs in <10% of patients.
- Caused by excess production of humoral factors like serotonin and tachykinins.
- Symptoms:
  - Cutaneous flushing (80%).
  - Diarrhea (76%).
  - Hepatomegaly (71%).
  - Cardiac lesions, mainly right-sided heart valvular disease (41–70%).
  - Asthma-like symptoms (25%).
- Types of Flushing:
  1. Diffuse erythematous: Short-lived, affects face, neck, upper chest.
  2. Violaceous: Longer attacks, possible permanent cyanotic flush.
  3. Prolonged flushes: Lasting up to 2–3 days, involving the entire body.
  4. Bright-red patchy flushing: Typically seen with gastric NETs.
- Cardiac Lesions:
  - Commonly involve the right side of the heart.
  - Lesions include pulmonary stenosis, tricuspid insufficiency, and tricuspid stenosis.
- Diarrhea:
  - Episodic, watery, often explosive.
  - Caused by increased serotonin levels.
- Asthma:
  - Bronchospasm occurring during flushing episodes.
  - Mediated by serotonin and bradykinin.

Diagnosis

Laboratory Tests:
- 24-hour Urinary 5-HIAA:
  - Measures metabolite of serotonin.
  - Highly specific for carcinoid tumors.
- Serum Chromogranin A (CgA):
  - Elevated in >80% of patients.
  - Used for diagnosis and surveillance.
  - N-terminal pro-brain natriuretic peptide may be combined with CgA for prognostic purposes.
Imaging Studies:
- Computed Tomography (CT) Scan:
  - Identifies tumor size, mesenteric invasion, regional lymph node involvement.
  - May show a solid mass with spiculated borders and radiating strands.
- Magnetic Resonance Imaging (MRI):
  - Particularly useful for detecting liver metastases.
- Functional Nuclear Imaging:
  - Octreotide Scans:
    - Uses radiolabeled somatostatin analogs.
    - High sensitivity for somatostatin receptor-positive tumors.
  - Positron Emission Tomography (PET):
    - 18F-FDG PET: Limited to high-grade NETs.
    - 68Ga-DOTATATE PET/CT:
      - Higher sensitivity and specificity.
      - Detects primary tumors and metastases effectively.
  - 64Cu-DOTATATE PET/CT:
    - FDA-approved diagnostic tool with better lesion detection and longer scanning window.

Treatment

Surgical Therapy

Indications:
- Tumors <1 cm without lymph node metastasis: Segmental intestinal resection.
- Tumors >1 cm, multiple tumors, or with lymph node metastasis: Wide excision of bowel and mesentery.
- Terminal ileum lesions: Best treated by right hemicolectomy.
- Small duodenal tumors: Can be locally excised; extensive lesions may require pancreaticoduodenectomy.
Laparoscopic Approach:
- Safe and feasible for selected patients.
- Associated with similar R0 resection rates, less morbidity, and shorter hospital stay compared to open surgery.
Management of Carcinoid Crisis:
- Caution during anesthesia to prevent crisis.
- Treated with IV octreotide: 50–100 μg bolus, then infusion at 50 μg/hr.
Mesenteric Disease Management:
- Thorough exploration for multicentric lesions.
- Dissection of tumor off mesenteric vessels while preserving blood supply.
- Mesenteric debulking provides significant survival advantage and symptom relief.
Debulking Surgery:
- Indicated even in widespread metastatic disease.
- Provides symptomatic relief and improves survival.
- Liver Metastases:
  - Metastasectomy is an option for limited hepatic involvement.
  - Transarterial chemoembolization or radioembolization for unresectable cases.
  - Hepatic transplantation has high recurrence rates and is limited in use.

Medical Therapy

Somatostatin Analogs (SSAs):
- First-line treatment for controlling symptoms.
- Includes octreotide and lanreotide (and their depot formulations).
- Relieve symptoms in >70% of patients.
- Antiproliferative Effect:
  - PROMID Trial: Octreotide LAR delayed tumor progression.
  - CLARINET Trial: Lanreotide prolonged progression-free survival.
Treatment of SSA-Refractory Disease:
- Everolimus:
  - An mTOR inhibitor approved for unresectable, advanced, or metastatic NETs.
  - RADIANT-4 Trial: Improved progression-free survival from 3.9 to 11 months.
  - Side effects include stomatitis, diarrhea, and fatigue.
Interferon Alpha:
- Used previously but limited by side effects.
- Pegylated Interferon Alpha-2b has more tolerable side effects.
- May be combined with SSAs for synergistic effect.
Treatment of Carcinoid Syndrome:
- Telotristat Etiprate:
  - A serotonin synthesis inhibitor.
  - Reduces bowel movements in SSA-refractory diarrhea.
  - TELESTAR Trial: 35% reduction in daily bowel movements.
- Serotonin Receptor Antagonists:
  - Examples include ondansetron, ketanserin, and cyproheptadine.
Chemotherapy:
- Historically used combinations like streptozotocin, 5-FU, and cyclophosphamide.
- Limited to patients with G2 metastatic disease unresponsive to other therapies.
- Temozolomide with capecitabine shows promise in well-differentiated metastatic NETs.
- Cisplatin and Etoposide used in poorly differentiated NECs.

Prognosis

Best prognosis among small bowel tumors.
Localized Disease: Near 100% survival rate after resection.
Regional Disease: ~65% 5-year survival.
Distant Metastasis: 25–35% 5-year survival.
Factors Affecting Prognosis:
- Elevated CgA levels indicate poorer outcomes.
- Metastatic disease at diagnosis occurs in 20–50% of patients.
- Tumor recurrence in 40–60% of cases.
Palliative Care:
- Even with metastatic disease, extensive resection may provide long-term palliation due to slow tumor growth.