Gastrointestinal NeuroendocrineTumors¶
Chapter 89 | Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 89
Key Clinical Points¶
- GI NETs are classified as extrapancreatic (carcinoid) or pancreatic based on origin.
- Grading is determined by mitotic count and Ki-67 index (grades 1–3).
- Functional NETs secrete hormones (e.g., insulinoma, gastrinoma), while nonfunctional ones are asymptomatic until metastasis.
- MEN1 syndrome is the most common inherited condition linked to NETs.
- Diagnosis involves chromogranin A, 5-HIAA, and somatostatin receptor imaging.
- Surgical resection is primary for localized disease; somatostatin analogues manage functional tumors.
- Appendiceal NETs <2 cm have low metastasis risk and may require only appendectomy.
- Well-differentiated NETs (e.g., small intestine) show improved survival compared to historical data.
- Somatostatin receptor scintigraphy shows >90% of NETs express receptors; 68Ga dotatate PET has high sensitivity for primary and metastatic disease.
- Telotristat ethyl is specifically used to treat carcinoid syndrome diarrhea.
1. DEFINITION & OVERVIEW¶
Gastrointestinal neuroendocrine tumors (NETs) are classified by site and differentiation:
• Extrapancreatic NETs: Historically called carcinoid tumors; arise in stomach, small intestine, appendix, and rectum. • Pancreatic NETs: Subcategorized as functional (hormone-secreting) or nonfunctional (asymptomatic until metastasis).
Grading is determined by mitotic count and Ki-67 index:
• Grade 1: <2 mitoses/10 HPF, Ki-67 <3% • Grade 2: 2–20 mitoses/10 HPF, Ki-67 3–20% • Grade 3: >20 mitoses/10 HPF, Ki-67 >20%
Definition (Harrison's 22e): Gastroenteropancreatic neuroendocrine tumors comprise the majority of neuroendocrine tumors, and recent analyses suggest the incidence in this subgroup has risen proportionately and continues to rise.
1.1 Classification by Site¶
• Extrapancreatic: Stomach, small intestine, appendix, rectum. • Pancreatic: Functional (insulinoma, gastrinoma) vs nonfunctional. • Rare Secretions: Somatostatin, VIP, ACTH, or PTH.
Refer to Table 89-1 for detailed histologic classification including differentiation and grade.
1.2 Classification by Differentiation and Grade¶
• Well-differentiated NETs: Monotonous sheets of small round cells with uniform nuclei. • Poorly differentiated (carcinoid): Pleomorphic cells, high mitotic count. • Immunohistochemistry: Positive for chromogranin A/synaptophysin. • Ultrastructure: Electron-dense neurosecretory granules.
2. EPIDEMIOLOGY¶
Incidence and trends:
• SEER data (1973–2012): 6.4-fold increase in overall NET incidence. • Estimated prevalence: >170,000 patients with diagnosed NETs. • Gastroenteropancreatic NETs account for the majority of all NETs.
Risk factors:
• Environmental factors: No clear link to diet, tobacco, or alcohol. • Inherited syndromes: 5–10% of NETs occur in inherited conditions (MEN1, VHL, NF1).
2.1 Risk Factors¶
• No clear association with lifestyle factors. • Inherited syndromes: ◦ MEN1 (40–50% of cases) ◦ VHL (<5%) ◦ NF1 (<5%)
2.2 Trends¶
• Age-adjusted incidence in US increased from 1975–2015. • Gastroenteropancreatic NETs show the steepest increase (3-fold rise).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Genetic alterations:
• Pancreatic NETs: 44% have MEN1 mutations; 43% have DAXX/ATRX mutations. • mTOR pathway mutations in 15% of pancreatic NETs. • Extrapancreatic NETs: Rare recurrent mutations (CDKN1B in 8% of small intestinal NETs).
Inherited syndromes:
• MEN1: Mutation in menin gene (chromosome 11q13). Patients develop pancreatic NETs, hyperparathyroidism, and pituitary adenomas. • VHL: Chromosome 3p25 mutation; associated with renal cancer, hemangioblastomas, and rare pancreatic NETs.
3.1 Inherited Genetic Syndromes¶
• MEN1 syndrome: Mutation in menin gene (chromosome 11q13). Patients develop pancreatic NETs, hyperparathyroidism, and pituitary adenomas. • VHL syndrome: Chromosome 3p25 mutation; associated with renal cancer, hemangioblastomas, and rare pancreatic NETs. • NF1: Neurofibromin mutations; increased risk of both pancreatic and extrapancreatic NETs.
3.2 Sporadic Mutations¶
• Small intestinal NETs: Loss of chromosome 18, epigenetic changes (clinical significance uncertain). • Familial small intestinal NETs: Multiple synchronous tumors; no identified mutation in most cases.
4. CLINICAL FEATURES¶
Functional vs nonfunctional tumors:
• Functional (20% of pancreatic): Hormone-related symptoms (hypoglycemia, diarrhea, flushing). • Nonfunctional (80% of pancreatic): Asymptomatic until metastasis; diagnosed incidentally or with abdominal pain/weight loss.
Carcinoid syndrome:
• Symptoms: Flushing (face/neck erythema), diarrhea, right-sided valvular heart disease. • Triggers: Stress, alcohol, cheese. • Consequences: Diarrhea → dehydration, hypokalemia, achlorhydria.
4.1 Functional Pancreatic NETs¶
• Insulinoma: Hypoglycemia with confusion, coma; weight gain. • Glucagonoma: Necrolytic migratory erythema (NME), glucose intolerance, weight loss. • Gastrinoma: Zollinger-Ellison syndrome (peptic ulcers, diarrhea). • VIPoma: Verner-Morrison syndrome (watery diarrhea, hypokalemia, achlorhydria). • ACTHoma: Cushing's syndrome (hyperglycemia, weight gain, hypokalemia).
4.2 Nonfunctional Pancreatic NETs¶
• Asymptomatic until metastasis. • Often discovered on imaging for unrelated conditions or with abdominal pain/weight loss.
4.3 Gastric NETs¶
• Type 1: Chronic atrophic gastritis, pernicious anemia, elevated gastrin. • Type 2: Associated with gastrinoma; multifocal tumors. • Type 3: Solitary tumors, normal gastrin levels, aggressive behavior.
4.4 Extrapancreatic NETs¶
• Small bowel NETs: Terminal ileum origin; difficult to diagnose early; associated with mesenteric fibrosis. • Appendiceal NETs: Incidental finding in appendectomy specimens (<2 cm diameter, low metastasis risk). • Rectal NETs: Common in Asia (up to 90% of NETs); small size (<1 cm), rarely metastatic.
5. DIFFERENTIAL DIAGNOSIS¶
Insulinoma mimics:
• Severe liver disease • Alcoholism • Surreptitious insulin use
Gastrinoma mimics:
• Achlorhydria (chronic atrophic gastritis) • PPI use
Carcinoid syndrome mimics:
• Systemic mastocytosis • Chronic laxative/diuretic abuse
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic approach:
-
Laboratory Markers: • Chromogranin A: Elevated in metastatic NETs (Note: Not specific; elevated in PPI use, renal failure). • 5-HIAA: Urinary serotonin metabolite for carcinoid syndrome. • Plasma markers: ◦ Glucagon (>1000 pg/mL) → confirms glucagonoma. ◦ Somatostatin → indicates somatostatinoma.
-
Imaging Modalities: • CT/MRI: Standard for anatomical assessment. • Somatostatin receptor scintigraphy: >90% of NETs express receptors. • 68Ga dotatate PET: High sensitivity for primary and metastatic disease. • FDG PET: ◦ Low sensitivity in well-differentiated NETs. ◦ Positive in high-grade tumors.
6.1 Laboratory Markers¶
• Chromogranin A: Elevated in metastatic NETs (not specific). • 5-HIAA: Urinary serotonin metabolite for carcinoid syndrome. • Plasma glucagon: >1000 pg/mL confirms glucagonoma. • Plasma somatostatin: Elevated in somatostatinoma.
6.2 Imaging Modalities¶
• CT/MRI: Standard for anatomical assessment. • Somatostatin receptor scintigraphy: >90% of NETs express receptors. • 68Ga dotatate PET: High sensitivity for primary and metastatic disease. • FDG PET: Low sensitivity in well-differentiated NETs.
6.3 Diagnostic Criteria for Specific Syndromes¶
• Insulinoma: Fasting hyperinsulinemia with elevated proinsulin/C-peptide. • Gastrinoma: Fasting hypergastrinemia. • Glucagonoma: Plasma glucagon >1000 pg/mL. • VIPoma: Elevated plasma VIP. • Somatostatinoma: Elevated plasma somatostatin. • Carcinoid syndrome: Elevated 5-HIAA.
7. MANAGEMENT & TREATMENT¶
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Localized Disease: • Primary treatment: Surgical resection. • Appendiceal NETs (<2 cm): Appendectomy alone sufficient (low metastasis risk). • Rectal NETs (>2 cm or lymph node involvement): Right colectomy.
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Functional Tumors: • Somatostatin analogues (octreotide, lanreotide) → control hormone secretion. • Telotristat ethyl → treatment for carcinoid syndrome diarrhea.
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Insulinoma Specific Management: • Diazoxide: Inhibits insulin release; side effects include sodium retention. • Everolimus: Improves glycemic control.
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Systemic & Advanced Therapy: • Chemotherapy: For high-grade NETs (e.g., streptozocin, doxorubicin). • Targeted therapy: Everolimus for advanced NETs. • Radioembolization: For liver metastases.
7.1 Pharmacologic Management¶
• Somatostatin analogues: ◦ Octreotide 25–50 μg SC TID. ◦ Lanreotide 30 mg IM every 4 weeks. • Telotristat ethyl: 125 mg PO TID for carcinoid syndrome diarrhea. • Everolimus: 10 mg PO daily for insulinoma.
7.2 Surgical Management¶
• Complete resection for localized disease (pancreatic NETs, appendiceal NETs <2 cm). • Right colectomy for rectal NETs with >2 cm diameter or lymph node involvement.
8. PROGNOSIS & COMPLICATIONS¶
Survival data:
• Small intestine NETs: 5-year survival ~50–70%. • Appendiceal NETs <2 cm: >90% 5-year survival.
Complications:
• Carcinoid heart disease: Right-sided valvular fibrosis (tricuspid/pulmonary). • Mesenteric fibrosis: Leads to intestinal obstruction or ischemia if vasculature is involved. • Metastatic disease: Prognosis worsens with increasing grade.
Clinical Findings¶
• Mesenteric Fibrosis: Often presents as a 'spoke and wheel' calcified mass on CT (Figure 4B).
9. SPECIAL CONSIDERATIONS¶
MEN1 syndrome:
• 40–50% of patients develop pancreatic NETs. • Surveillance: Annual endoscopic ultrasound, MRI, and biochemical testing.
Other syndromes:
• VHL: Pancreatic NETs occur in <5% of cases. • NF1: Increased risk of both pancreatic and extrapancreatic NETs.
10. KEY PEARLS & CLINICAL TRAPS¶
Diagnostic pitfalls:
• Chromogranin A elevation eq specific (can be caused by PPI use or renal failure). • 5-HIAA elevation is not diagnostic of carcinoid syndrome on its own.
Treatment traps:
• Somatostatin analogues → worsen hypoglycemia in insulinoma patients. • Appendiceal NETs <2 cm rarely metastasize; avoid over-treatment/unnecessary surgery.
Trial Data Summary (Tables 89-3 & 89-5):
• Lanreotide: 65% vs 33% at 2 years (p <0.001). • Cabozantinib: Significant improvement in progression-free survival for both epNET and pNET. • Sunitinib: 11.4 vs 5.5 months (p <0.001). • Temozolomide/capecitabine: 22.7 vs 14.4 months (p = 0.021). • Everolimus + octreotide: 16.4 vs 11.3 months. • Surufatinib: 9.2 vs 3.8 months (p <0.0001). • Pazopanib: 11.6 vs 8.5 months (p <0.005). • 177Lutetium dotatate: 65.2 vs 10.8% at 20 months (p <0.001).
Reference Tables¶
TABLE 88-4 Combination Chemotherapy Regimens That Have an Impact on Survival in Stage IV Disease¶
Harrison's 22e, p.676
| STUDY DESIGN (AUTHOR/REF) | NO. OF PATIENTS |
MEDIAN OVERALL SURVIVAL (MONTHS) |
|---|---|---|
| Gemcitabine + erlotinib vs gemcitabine (Moore et al: J Clin Oncol 26:1960, 2007) |
569 | 6.24 vs 5.91 (HR 0.82; 95% CI 0.69–0.99; p = .038) |
| 342 | ||
| Nab-paclitaxel + gemcitabine vs gemcitabine (Von Hoff et al: N Eng J Med 369:1691, 2013) |
861 | 8.5 vs 6.7 (HR 0.72; 95% CI 0.62–0.83; p <.001a |
| 417 | ||
| NALIRIFOX (nanoliposomal irinotecan, 5-fluorouracil, folinic acid, oxaliplatin) vs nab-paclitaxel and gemcitabine (Wainberg et al: Lancet 402:1272, 2023) |
770 | 11.1 vs 9.2 (HR 0.83; 95% CI 0.70–0.99; p = .036) |
| 89 | Gastrointestinal Neuroendocrine Tumors Matthew H. Kulke |
TABLE 89-1 Histologic Classification of Neuroendocrine Tumors CLASSIFICATION Neuroendocrine tumor Neuroendocrine tumor…¶
Harrison's 22e, p.677
| CLASSIFICATION | DIFFERENTIATION | GRADE | MITOTIC COUNT | KI-67 |
|---|---|---|---|---|
| Neuroendocrine tumor | Well differentiated | Low grade (grade 1) | <2 per 10 HPF | <3% |
| Well differentiated | Intermediate grade (grade 2) | 2–20 per 10 HPF | ||
| Neuroendocrine tumor | Well differentiated | High grade (grade 3) | >20 per 10 HPF | >20% |
| Poorly differentiated | High grade (grade 3) | >20 per 10 HPF |
TABLE 89-2 Clinical Presentation and Management of Secretory Syndromes Associated with Neuroendocrine Tumors¶
Harrison's 22e, p.678
| CLINICAL SYMPTOMS AND MANIFESTATIONS |
TREATMENT OPTIONS TO CONTROL SECRETORY SYMPTOMS |
|
|---|---|---|
| Pancreatic Neuroendocrine Tumors | ||
| Gastrinoma (generally located in “gastrinoma triangle”) |
Zollinger-Ellison syndrome: gastroesophageal reflux, peptic ulcer disease, diarrhea |
Proton pump inhibitors, somatostatin analogues |
| Hypoglycemia leading to confusion, lethargy, coma; weight gain |
||
| Glucagonoma | Skin rash (necrolytic migratory erythema), glucose intolerance, weight loss |
Somatostatin analogues |
| Verner-Morrison syndrome: watery diarrhea, hypokalemia, achlorhydria |
||
| ACTHoma | Cushing’s syndrome: hyperglycemia, weight gain, hypokalemia |
Ketoconazole, metyrapone, consider adrenalectomy |
| Extrapancreatic Gastrointestinal Neuroendocrine Tumors |
TABLE 89-3 Selected Randomized Trials of Therapeutic Agents for the Treatment of Advanced Neuroendocrine Tumors (NETs)¶
Harrison's 22e, p.684
| TUMOR TYPE | NUMBER OF PATIENTS |
PROGRESSION-FREE SURVIVAL |
|---|---|---|
| Pancreatic and Extrapancreatic NETs | ||
| Lanreotide vs placebo (CLARINET) |
204 | 65% vs 33% at 2 years (p <.001) |
| 226 (limited to histologic grade 2 and 3 tumors) |
||
| Cabozantinib vs placebo (CABINET) |
298 (203 extrapancreatic NETs [epNET] and 95 pancreatic NETs [pNET]) |
8.5 vs 4 months (epNET); 13.8 vs 4.5 months (pNET) (p <.0001 for both cohorts) |
| Pancreatic NET | ||
| 410 | ||
| Sunitinib vs placebo | 171 | 11.4 vs 5.5 months (p <.001) |
| 264 | ||
| Temozolomide/ capecitabine vs temozolomide |
144 | 22.7 vs 14.4 months (p = .021) |
| Extrapancreatic NET | ||
| 85 | ||
| Everolimus + octreotide vs octreotide (RADIANT 2) |
429 | 16.4 vs 11.3 months |
| 302 | ||
| Surufatinib vs placebo | 198 | 9.2 vs 3.8 months (p <.0001) |
| 171 | ||
| 177-Lutetium dotatate vs octreotide (NETTER 1) |
230 | 65.2 vs 10.8% at 20 months (p <.001) |